Heterocyclic compound

ABSTRACT

The present invention aims to provide a heterocyclic compound having an AMPA receptor potentiator effect, which is expected to be useful as an agent for the prophylaxis or treatment of depression, Alzheimer&#39;s disease, schizophrenia, attention deficit hyperactivity disorder (ADHD) and the like. 
     The present invention relates to a compound represented by the formula (I): 
     
       
         
         
             
             
         
       
     
     wherein each symbol is as described in the specification, or a salt thereof.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound, particularly aheterocyclic compound having an AMPA(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptorpotentiator effect, which is expected to be useful as an agent for theprophylaxis or treatment of depression, Alzheimer's disease,schizophrenia, attention deficit hyperactivity disorder (ADHD) and thelike.

BACKGROUND OF THE INVENTION

Glutamic acid is an excitatory neurotransmitter most abundantly presentin the central nervous system of mammals. Glutamic acid plays animportant role in the cognition, mood and control of motor function, andthe neurotransmission thereof becomes unstable in psychiatric diseasesand neuropathy. Glutamic acid receptors are classified into ionligand-gated ion channel and G protein conjugated-type receptor, and theligand-gated ion channel is further classified intoα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor,N-methyl-D-aspartic acid (NMDA) receptor and kainic acid (KA) receptor(Non-patent Document 1).

AMPA receptor is one kind of receptor for excitatory neurotransmitterglutamic acid, and was named based on selective activation of thereceptor by AMPA. AMPA receptor consists of 4 subunits (GluR1, GluR2,GluR3, GluR4). Each subunit contains flip type and flop type splicingvariants. In the living body, AMPA receptor forms a homogeneous orheterogeneous tetramer consisting of such subunits. It has been reportedthat the physiological property of AMPA receptor varies depending on thesubunits constituting the receptor (Non-patent Documents 1, 2 and 3).

The importance of AMPA receptor in brain physiology is well known, and acompound having an AMPA receptor potentiator effect is expected to beuseful as an agent for the prophylaxis or treatment of psychiatricdiseases, neurodegenerative disease, memory disorders, sleep disorder,genetic diseases associated with psychiatric disorders and cognitiveimpairment, stroke, hearing loss and the like (Non-patent Documents 4 to10).

As a heterocyclic compound having an AMPA receptor potentiator effect,the following compounds are disclosed.

-   (1) Patent Document 1 discloses a compound represented by the    following formula:

wherein each symbol is as defined in the document.

-   (2) Patent Document 2 discloses a compound represented by the    following formula:

wherein each symbol is as defined in the document.

-   (3) Patent Document 3 discloses a compound represented by the    following formula:

wherein each symbol is as defined in the document.

-   (4) Patent Document 4 discloses a compound represented by the    following formula:

wherein each symbol is as defined in the document.

-   (5) Patent Document 5 discloses a compound represented by the    following formula:

wherein each symbol is as defined in the document.

-   (6) Patent Document 6 discloses a compound represented by the    following formula:

wherein each symbol is as defined in the document.

-   (7) Patent Document 7 discloses a compound represented by the    following formula:

wherein each symbol is as defined in the document.

DOCUMENT LIST Patent Document

-   Patent Document 1: WO 2009/119088-   Patent Document 2: WO 2010/140339-   Patent Document 3: WO 2011/036889-   Patent Document 4: WO 2011/036885-   Patent Document 5: WO 2012/020848-   Patent Document 6: WO 2012/137982-   Patent Document 7: WO 2013/118845

Non-Patent Document

-   Non-Patent Document 1: Pharmacological Reviews, Vol. 51, p. 7-61,    1999-   Non-Patent Document 2: Neuropharmacology, Vol. 34, p. 123-139, 1995-   Non-Patent Document 3: Annual Review of Neuroscience, Vol. 25, 5 p.    103-126, 2002-   Non-Patent Document 4: CNS & Neurological Disorders-Drug Targets,    Vol. 7, p. 129-143, 2008-   Non-Patent Document 5: Current Opinion in Drug Discovery and    Development, Vol. 9, p. 571-579, 2006-   Non-Patent Document 6: Journal of Neuroscience, Vol. 27, p.    10912-10917, 2007-   Non-Patent Document 7: Journal of Neuroscience, Vol. 27, p.    5338-5348, 2007-   Non-Patent Document 8: Neurobiology of Disease, Vol. 47, p. 210-215,    2012-   Non-Patent Document 9: Journal of Neuroscience, Vol. 31, p.    3766-3775, 2011-   Non-Patent Document 10: Journal of Neurophysiology, Vol. 94, p.    1814-1824, 2005

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention aims to provide a heterocyclic compound having anAMPA receptor potentiator effect, which is expected to be useful as anagent for the prophylaxis or treatment of depression, Alzheimer'sdisease, schizophrenia, attention deficit hyperactivity disorder (ADHD)and the like (AMPA receptor potentiator; AMPA receptor potentiator issometimes also referred to as AMPA receptor positive modulator,AMPAkine, AMPA receptor allosteric modulator, AMPA receptor positiveallosteric modulator or positive allosteric modulator of AMPA receptor).

Means of Solving the Problems

The present inventors have found that a compound represented by thefollowing formula (I) or a salt thereof (in the present specification,sometimes to be referred to as compound (I) or simply as the compound ofthe present invention) may have an AMPA receptor potentiator effect, andconducted further studies, which resulted in the completion of thepresent invention. In this specification, compound (I) and a prodrugthereof are also sometimes collectively referred to as the compound ofthe present invention.

Accordingly, the present invention provides the following.

-   [1]

A compound represented by the formula (I):

wherein

-   R¹ and R² are each independently a hydrogen atom or a substituent,    or R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom, an optionally further substituted    non-aromatic nitrogen-containing heterocycle,-   X is CR⁴ or N,-   R³, R⁴, R⁵ and R⁶ are each independently a hydrogen atom, a halogen    atom, an optionally substituted C₁₋₆ alkyl group or an optionally    substituted C₁₋₆ alkoxy group, and-   Ring A is a 6-membered aromatic ring optionally further substituted    by 1 to 4 substituents selected from (i) a halogen atom, (ii) a C₁₋₆    alkyl group and (iii) a C₁₋₆ alkoxy group, or a salt thereof.-   [2]

The compound or salt of the above-mentioned [1], wherein R¹ and R² areeach independently

-   (1) a hydrogen atom,-   (2) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituents    selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkoxy group,    -   (e) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to 3        cyano groups, and    -   (f) a 3-to 14-membered non-aromatic heterocyclic group,-   (3) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to 3 C₁₋₆    alkyl groups optionally substituted by 1 to 3 halogen atoms, or-   (4) a 3-to 14-membered non-aromatic heterocyclic group, or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom, a 3-to 14-membered non-aromatic    nitrogen-containing heterocycle optionally further substituted by 1    to 3 substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom, and        -   (ii) a hydroxy group,    -   (e) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms, and    -   (f) a C₃₋₁₀ cycloalkyl group;-   R³ is-   (1) a hydrogen atom,-   (2) a halogen atom, or-   (3) a C₁₋₆ alkyl group;-   X is CH or N;-   R⁵ is a hydrogen atom;-   R⁶ is a hydrogen atom; and-   Ring A is a benzene ring optionally further substituted by 1 or 2    halogen atoms.-   [3]

The compound or salt of the above-mentioned [1], wherein R¹ and R² areeach independently

-   (1) a hydrogen atom,-   (2) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituents    selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkoxy group,    -   (e) a C₃₋₆ cycloalkyl group optionally substituted by 1 to 3        cyano groups, and    -   (f) an oxetanyl group,-   (3) a C₃₋₆ cycloalkyl group optionally substituted by 1 to 3 0₁-₆    alkyl groups optionally substituted by 1 to 3 halogen atoms,-   (4) a tetrahydrofuryl group, or-   (5) a tetrahydropyranyl group, or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom,-   (1) a morpholine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group, and    -   (c) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms,-   (2) a pyrrolidine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom, and        -   (ii) a hydroxy group, and    -   (e) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogen        atoms,-   (3) a piperidine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom,    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen        atoms, and    -   (e) a C₁₋₆ alkoxy group,-   (4) an azetidine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom,    -   (b) a hydroxy group,    -   (c) a C₁₋₆ alkyl group,    -   (d) a C₁₋₆ alkoxy group, and    -   (e) a C₃₋₆ cycloalkyl group,-   (5) an oxazepane ring optionally further substituted by 1 to 3    halogen atoms,-   (6) a 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine ring,-   (7) a 1-oxa-7-azaspiro[3.5]nonane ring, or-   (8) a 2-oxa-5-azabicyclo[4.1.0]heptane ring;-   R³ is-   (1) a hydrogen atom,-   (2) a halogen atom, or-   (3) a C₁₋₆ alkyl group;-   X is CH or N;-   R⁵ is a hydrogen atom;-   R⁶ is a hydrogen atom; and-   Ring A is a benzene ring optionally further substituted by 1 or 2    halogen atoms.-   [4]

The compound or salt of the above-mentioned [1], wherein

-   R¹ is a hydrogen atom, and-   R² is a tetrahydropyranyl group, or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom,-   (1) a morpholine ring optionally further substituted by 1 to 3 C₁₋₆    alkyl groups, or-   (2) a pyrrolidine ring optionally further substituted by 1 to 3    cyano groups;-   R³ is-   (1) a hydrogen atom,-   (2) a halogen atom, or-   (3) a C₁₋₃ alkyl group;-   X is CH;-   R⁵ is a hydrogen atom;-   R⁶ is a hydrogen atom; and-   Ring A is a benzene ring.-   [5]

The compound or salt of the above-mentioned [1], wherein

-   R¹ is a hydrogen atom, and-   R² is a tetrahydropyranyl group, or R¹ and R² are bonded to each    other to form, together with the adjacent nitrogen atom, a    morpholine ring optionally further substituted by one C₁₋₆ alkyl    group;-   R³ is-   (1) a halogen atom, or-   (2) a C₁₋₃ alkyl group;-   X is CH;-   R⁵ is a hydrogen atom;-   R⁶ is a hydrogen atom; and-   Ring A is a benzene ring.-   [6]    3-Bromo-9-(4-(morpholin-4-ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one,    or a salt thereof.-   [7]    3-Bromo-9-(4-M2S)-2-methylmorpholin-4-yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one,    or a salt thereof.-   [8]    4-(3-Methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3S)-tetrahydro-2H-pyran-3-yl)benzamide,    or a salt thereof.-   [9] A medicament comprising the compound or salt of any of the    above-mentioned [1] to [8].-   [10] The medicament of the above-mentioned [9], which is an AMPA    receptor potentiator.-   [11] The medicament of the above-mentioned [9], which is an agent    for the prophylaxis or treatment of depression, Alzheimer's disease,    schizophrenia or attention deficit hyperactivity disorder.

[12] The compound or salt of any of the above-mentioned [1] to [8] foruse in the prophylaxis or treatment of depression, Alzheimer's disease,schizophrenia or attention deficit hyperactivity disorder.

-   [13] A method of enhancing AMPA receptor function in a mammal, which    comprises administering an effective amount of the compound or salt    of any of the above-mentioned [1] to [8] to the mammal.-   [14] A method for the prophylaxis or treatment of depression,    schizophrenia, Alzheimer's disease or attention deficit    hyperactivity disorder in a mammal, which comprises administering an    effective amount of the compound or salt of any of the    above-mentioned [1] to [8] to the mammal.-   [15] Use of the compound or salt of any of the above-mentioned [1]    to [8] for the manufacture of an agent for the prophylaxis or    treatment of depression, Alzheimer's disease, schizophrenia or    attention deficit hyperactivity disorder.

Effect of the Invention

According to the present invention, a useful compound having an AMPAreceptor potentiator effect, which is expected to be useful as an agentfor the prophylaxis or treatment of depression, Alzheimer's disease,schizophrenia, attention deficit hyperactivity disorder (ADHD) and thelike, can be provided.

(DETAILED DESCRIPTION OF THE INVENTION)

The present invention is explained in detail in the following.

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichioromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the ^(“C) ₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “01_6 alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichioroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5-to 14-membered aromaticheterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl, thenoyland furoyl.

In the present specification, examples of the “3-to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or alkyl-carbamoylgroup” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a 0₂-₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following Substituent group A.

[Substituent group A]

-   (1) a halogen atom,-   (2) a nitro group,-   (3) a cyano group,-   (4) an oxo group,-   (5) a hydroxy group,-   (6) an optionally halogenated C₁₋₆ alkoxy group,-   (7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),-   (8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy).-   (9) a 5-to 14-membered aromatic heterocyclyloxy group (e.g.,    pyridyloxy),-   (10) a 3-to 14-membered non-aromatic heterocyclyloxy group (e.g.,    morpholinyloxy, piperidinyloxy),-   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),-   (12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy,    1-naphthoyloxy, 2-naphthoyloxy),-   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,    ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),-   (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,    methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,    diethylcarbamoyloxy),-   (15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,    naphthylcarbamoyloxy),-   (16) a 5-to 14-membered aromatic heterocyclylcarbonyloxy group    (e.g., nicotinoyloxy),-   (17) a 3-to 14-membered non-aromatic heterocyclylcarbonyloxy group    (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),-   (18) an optionally halogenated C₁-₆ alkylsulfonyloxy group (e.g.,    methylsulfonyloxy, trifluoromethylsulfonyloxy),-   (19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆    alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),-   (20) an optionally halogenated C₁₋₆ alkylthio group,-   (21) a 5-to 14-membered aromatic heterocyclic group,-   (22) a 3-to 14-membered non-aromatic heterocyclic group,-   (23) a formyl group,-   (24) a carboxy group,-   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,-   (26) a C₆₋₁₄ aryl-carbonyl group,-   (27) a 5-to 14-membered aromatic heterocyclylcarbonyl group,-   (28) a 3-to 14-membered non-aromatic heterocyclylcarbonyl group,-   (29) a C₁₋₆ alkoxy-carbonyl group,-   (30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,    1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),-   (31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,    phenethyloxycarbonyl),-   (32) a carbamoyl group,-   (33) a thiocarbamoyl group,-   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,-   (35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),-   (36) a 5-to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,    pyridylcarbamoyl, thienylcarbamoyl),-   (37) a 3-to 14-membered non-aromatic heterocyclylcarbamoyl group    (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),-   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,-   (39) a C₆₋₁₄ arylsulfonyl group,-   (40) a 5-to 14-membered aromatic heterocyclylsulfonyl group5 (e.g.,    pyridylsulfonyl, thienylsulfonyl),-   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,-   (42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,    1-naphthylsulfinyl, 2-naphthylsulfinyl),-   (43) a 5-to 14-membered aromatic heterocyclylsulfinyl group (e.g.,    pyridylsulfinyl, thienylsulfinyl),-   (44) an amino group,-   (45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino,    ethylamino, propylamino, isopropylamino, butylamino, dimethylamino,    diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino),-   (46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),-   (47) a 5-to 14-membered aromatic heterocyclylamino group (e.g.,    pyridylamino),-   (48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),-   (49) a formylamino group,-   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,    propanoylamino, butanoylamino),-   (51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl) amino group (e.g.,    N-acetyl-N-methylamino),-   (52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,    naphthylcarbonylamino),-   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,    ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,    tert-butoxycarbonylamino),-   (54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,    benzyloxycarbonylamino),-   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,    ethylsulfonylamino),-   (56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a    C₁₋₆ alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),-   (57) an optionally halogenated C₁₋₆ alkyl group,-   (58) a C₂₋₆ alkenyl group,-   (59) a C₂₋₆ alkynyl group,-   (60) a C₃₋₁₀ cycloalkyl group,-   (61) a C₃₋₁₀ cycloalkenyl group, and-   (62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7-to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5-to 14-membered aromatic heterocyclic group”)include a 5-to 14-membered (preferably 5-to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” 5 include 5-or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and8-to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3-to 14-membered non-aromatic heterocyclic group”)include a 3-to 14-membered (preferably 4-to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9-to 14-membered fused polycyclic (preferably bi or tricyclic)non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-p-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7-to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the above-mentioned Substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C7-16 aralkyl group, a 5-to14-membered aromatic heterocyclic group and a 3-to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group. Preferableexamples of the “acyl group” include a formyl group, a carboxy group, aC₁₋₆ alkyl-carbonyl group, a C₂-₆ alkenyl-carbonyl group (e.g.,crotonoyl), a C₃₋₁₀ cycloalkyl-carbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5-to 14-membered aromatic heterocyclylcarbonylgroup, a 3-to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄ aryloxy-carbonyl group (e.g.,phenyloxycarbonyl, naphthyloxycarbonyl), a C₇₋₁₆ aralkyloxy-carbonylgroup (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), a carbamoylgroup, a mono- or di-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₂₋₆alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), a mono- ordi-C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- ordi-C₇₋₁₆ aralkyl-carbamoyl group, a 5-to 14-membered aromaticheterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), a thiocarbamoylgroup, a mono- or di-C₁₋₆ alkyl-thiocarbamoyl group (e.g.,methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- ordi-C₃₋₁₀ cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di^(-C) ₆₋₁₄ aryl-thiocarbamoylgroup (e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl,phenethylthiocarbamoyl), a 5-to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl), a sulfinogroup, a C₁₋₆ alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl),a sulfo group, a C₁₋₆ alkylsulfonyl group, a C₆₋₁₄ arylsulfonyl group, aphosphono group and a mono- or di-C₁₋₆ alkylphosphono group (e.g.,dimethylphosphono, diethylphosphono, diisopropylphosphono,dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5-to 14-membered aromatic heterocyclylcarbonylgroup, a 3-to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁-₆ alkoxy-carbonyl group, a 5-to 14-membered aromatic heterocyclicgroup, a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a C₁₋₆ alkylsulfonyl groupand a C₆₋₁₄ arylsulfonyl group, each of which optionally has 1 to 3substituents selected from Substituent group A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl) aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5-to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3-to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., −5 piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5-to 14-membered aromatic heterocyclylaminogroup (e.g., pyridylamino), a carbamoylamino group, a (mono- or di-C₁₋₆alkyl-carbamoyl) amino group (e.g., methylcarbamoylamino), a (mono- ordi-C₇₋₁₆ aralkyl-carbamoyl) amino group (e.g., benzylcarbamoylamino), aC₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,ethylsulfonylamino), a C₆₋₁₄ arylsulfonylamino group (e.g.,phenylsulfonylamino), a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl) amino group(e.g., N-acetyl-N-methylamino) and a (C₁₋₆ alkyl) (C₆₋₁₄ aryl-carbonyl)amino group (e.g., N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5-to 14-membered aromatic heterocyclylcarbonylgroup, a 3-to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a 5-to 14-membered aromatic heterocyclicgroup, a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group and amono- or di-C₇₋₁₆ aralkyl-carbamoyl group, each of which optionally has1 to 3 substituents selected from Substituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5-to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5-to 14-membered aromatic heterocyclylcarbonylgroup, a 3-to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a 5-to 14-membered aromatic heterocyclicgroup, a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group and amono- or di-C₇₋₁₆ aralkyl-carbamoyl group, each of which optionally has1 to 3 substituents selected from Substituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5-to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5-to 14-membered aromatic heterocyclylcarbonylgroup, a 3-to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a 5-to 14-membered aromatic heterocyclicgroup, a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group and amono- or di-C₇₋₁₆ aralkyl-carbamoyl group, each of which optionally has1 to 3 substituents selected from Substituent group A″.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5-to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxy group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5-to 14-membered aromatic heterocyclylcarbonylgroup, a 3-to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a 5-to 14-membered aromatic heterocyclicgroup, a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₇₋₁₆ aralkyl-carbamoyl group, a C₁₋₆ alkylsulfonyl groupand a C₆₋₁₄ arylsulfonyl group, each of which optionally has 1 to 3substituents selected from Substituent group A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5-to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3-to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5-to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5-to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from Substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (—SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5-to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromSubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

In the present specification, examples of the “non-aromatic heterocycle”include a 3-to 14-membered (preferably 4-to 10-membered) non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “non-aromatic heterocycle”include 3-to 8-membered monocyclic non-aromatic heterocycles such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline,pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole,tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine,tetrahydropyridine, dihydropyridine, dihydrothiopyran,tetrahydropyrimidine, tetrahydropyridazine, dihydropyran,tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine,azepane, diazepane, azepine, azocane, diazocane, oxepane and the like;and 9-to 14-membered fused polycyclic (preferably bi or tricyclic)non-aromatic heterocycles such as dihydrobenzofuran,dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole,dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene,tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, idoline,isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine,tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine,hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine,tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole,tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine,tetrahydrothioxanthene, octahydroisoquinoline and the like.

The definition of each symbol in the formula (I) is explained below.

R¹ and R² are each independently a hydrogen atom or a substituent, or R¹and R² are bonded to each other to form, together with the adjacentnitrogen atom, an optionally further substituted non-aromaticnitrogen-containing heterocycle.

The “substituent” represented by R¹ or R² is preferably

-   (1) an optionally substituted C₁₋₆ alkyl group (e.g., methyl, ethyl,    propyl),-   (2) an optionally substituted C₃₋₁₀ cycloalkyl group (e.g.,    cyclopropyl), or-   (3) an optionally substituted 3-to 14-membered non-aromatic    heterocyclic group (preferably a 3-to 8-membered monocyclic    non-aromatic heterocyclic group (e.g., tetrahydrofuryl,    tetrahydropyranyl)).

The “substituent” represented by R¹ or R² is more preferably

-   (1) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl) optionally    substituted by 1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),    -   (e) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl)        optionally substituted by 1 to 3 cyano groups, and    -   (f) a 3-to 14-membered non-aromatic heterocyclic group        (preferably a 3-to 8-membered monocyclic non-aromatic        heterocyclic group (e.g., oxetanyl)),-   (2) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl) optionally io    substituted by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl) optionally    substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or-   (3) a 3-to 14-membered non-aromatic heterocyclic group (preferably a    3-to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,    tetrahydrofuryl, tetrahydropyranyl)).

Examples of the “non-aromatic nitrogen-containing heterocycle” of the“optionally further substituted non-aromatic nitrogen-containingheterocycle” formed by R¹ and R² bonded to each other, together with theadjacent nitrogen atom, include a non-aromatic heterocycle containing atleast one nitrogen atom as a ring-constituting atom, from among the“non-aromatic heterocycle”.

The “non-aromatic nitrogen-containing heterocycle” includes a 6-to9-membered nitrogen-containing spiro ring (e.g.,1-oxa-7-azaspiro[3.5]nonane), and a 6-to 9-membered nitrogen-containingbridged ring (e.g., 2-oxa-5-azabicyclo[4.1.0]heptane).

Preferable examples of the “non-aromatic nitrogen-containingheterocycle” include a 3-to 14-membered monocyclic non-aromaticnitrogen-containing heterocycle (preferably a 3-to 8-membered monocyclicnon-aromatic nitrogen-containing heterocycle (e.g., azetidine,pyrrolidine, piperidine, morpholine, oxazepane (e.g., 1,4-oxazepane)), a9-to 14-membered fused polycyclic (preferably bi- or tri-cyclic)non-aromatic nitrogen-containing heterocycle (e.g.,2,3-dihydro-1H-pyrrolo[2,3-b]pyridine), a 6-to 9-memberednitrogen-containing Spiro ring (e.g., 1-oxa-7-azaspiro[3.5]nonane), a6-to 9-membered nitrogen-containing bridged ring (e.g.,2-oxa-5-azabicyclo[4.1.0]heptane)).

The “non-aromatic nitrogen-containing heterocycle” is preferably a 3-to8-membered monocyclic non-aromatic nitrogen-containing heterocycle(e.g., azetidine, pyrrolidine, piperidine, morpholine, oxazepane (e.g.,1,4-oxazepane)), a 9-to 14-membered fused polycyclic (preferably bi- ortri-cyclic) non-aromatic nitrogen-containing heterocycle (e.g.,2,3-dihydro-1H-pyrrolo[2,3-b]pyridine), a 6-to 9-memberednitrogen-containing Spiro ring (e.g., 1-oxa-7-azaspiro[3.5]nonane), or a6-to 9-membered nitrogen-containing bridged ring (e.g.,2-oxa-5-azabicyclo[4.1.0]heptane).

The “non-aromatic nitrogen-containing heterocycle” is more preferably amorpholine ring, a pyrrolidine ring, a piperidine ring, an azetidinering, an oxazepane ring (preferably 1,4-oxazepane), a2,3-dihydro-1H-pyrrolo[2,3-b]pyridine ring, a1-oxa-7-azaspiro[3.5]nonane ring or a 2-oxa-5-azabicyclo[4.1.0]heptanering.

The “non-aromatic nitrogen-containing heterocycle” is further morepreferably a morpholine ring, a pyrrolidine ring, a piperidine ring, anazetidine ring, an oxazepane ring (preferably 1,4-oxazepane), a2,3-dihydro-1H-pyrrolo[2,3-b]pyridine ring or a2-oxa-5-azabicyclo[4.1.0]heptane ring.

The “non-aromatic nitrogen-containing heterocycle” is still morepreferably a morpholine ring or a pyrrolidine ring. The “non-aromaticnitrogen-containing heterocycle” is particularly preferably a morpholinering.

The “non-aromatic nitrogen-containing heterocycle” of the “optionallyfurther substituted non-aromatic nitrogen-containing heterocycle” formedby R¹ and R² bonded to each other, together with the adjacent nitrogenatom, is optionally further substituted, at substitutable position(s),by substituent(s) selected from the above-mentioned Substituent Group A.The number of the substituents is, for example, 1 to 3. When the numberof the substituents is 2 or more, the respective substituents may be thesame or different. In addition, the Substituent Group A is optionallyfurther substituted by substituent(s) selected from the above-mentionedSubstituent Group A. The number of the substituents is, for example, 1to 3. When the number of the substituents is 2 or more, the respectivesubstituents may be the same or different.

Preferable examples of the “substituent” of the “non-aromaticnitrogen-containing heterocycle” include

-   -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a hydroxy group,    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (f) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl).

R¹ and R² are preferably each independently

-   (1) a hydrogen atom,-   (2) an optionally substituted C₁₋₆ alkyl group (e.g., methyl, ethyl,    propyl),-   (3) an optionally substituted C₃₋₁₀ cycloalkyl group (e.g.,    cyclopropyl), or-   (4) an optionally substituted 3-to 14-membered non-aromatic    heterocyclic group (preferably a 3-to 8-membered monocyclic    non-aromatic heterocyclic group (e.g., tetrahydrofuryl,    tetrahydropyranyl)), or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom, an optionally further substituted 3-to    14-membered non-aromatic nitrogen-containing heterocycle (preferably    a 3-to 8-membered monocyclic non-aromatic nitrogen-containing    heterocycle (e.g., azetidine, pyrrolidine, piperidine, morpholine,    oxazepane (e.g., 1,4-oxazepane)), a 9-to 14-membered fused    polycyclic (preferably bi- or tri-cyclic) non-aromatic    nitrogen-containing heterocycle (e.g.,    2,3-dihydro-1H-pyrrolo[2,3-b]pyridine), a 6-to 9-membered    nitrogen-containing spiro ring (e.g., 1-oxa-7-azaspiro[3.5]nonane),    a 6-to 9-membered nitrogen-containing bridged ring (e.g.,    2-oxa-5-azabicyclo[4.1.0]heptane)).

R¹ and R² are more preferably each independently

-   (1) a hydrogen atom,-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl) optionally    substituted by 1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁-6 alkoxy group (e.g., methoxy, ethoxy),    -   (e) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl)        optionally substituted by 1 to 3 cyano groups, and    -   (f) a 3-to 14-membered non-aromatic heterocyclic group        (preferably a 3-to 8-membered monocyclic non-aromatic        heterocyclic group (e.g., oxetanyl)),-   (3) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl) optionally    substituted by 1 to 3 01-6 alkyl groups (e.g., methyl) optionally    substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or-   (4) a 3-to 14-membered non-aromatic heterocyclic group (preferably a    3-to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,    tetrahydrofuryl, tetrahydropyranyl)), or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom, a 3-to 14-membered non-aromatic    nitrogen-containing heterocycle (preferably a 3-to 8-membered    monocyclic non-aromatic nitrogen-containing heterocycle (e.g.,    azetidine, pyrrolidine, piperidine, morpholine, oxazepane (e.g.,    1,4-oxazepane)), a 9-to 14-membered fused polycyclic (preferably bi-    or tri-cyclic) non-aromatic nitrogen-containing heterocycle (e.g.,    2,3-dihydro-1H-pyrrolo[2,3-b]pyridine), a 6-to 9-membered    nitrogen-containing Spiro ring (e.g., 1-oxa-7-azaspiro[3.5]nonane),    a 6-to 9-membered nitrogen-containing bridged ring (e.g.,    2-oxa-5-azabicyclo[4.1.0]heptane)) optionally further substituted by    1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a hydroxy group,    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (f) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl).

R¹ and R² are further more preferably each independently

-   (1) a hydrogen atom,-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl) optionally    substituted by 1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),    -   (e) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl)        optionally substituted by 1 to 3 cyano groups, and    -   (f) a 3-to 8-membered monocyclic non-aromatic heterocyclic group        (e.g., oxetanyl),-   (3) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl) optionally    substituted by 1 to 3 01-6 alkyl groups (e.g., methyl) optionally    substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or-   (4) a 3-to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., tetrahydrofuryl, tetrahydropyranyl), or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom,-   (1) a 3-to 8-membered monocyclic non-aromatic nitrogen-containing    heterocycle (e.g., azetidine, pyrrolidine, piperidine, morpholine,    oxazepane (e.g., 1,4-oxazepane)),-   (2) a 9-to 14-membered fused bi- or tri-cyclic non-aromatic    nitrogen-containing heterocycle (e.g.,    2,3-dihydro-1H-pyrrolo[2,3-b]pyridine),-   (3) a 6-to 9-membered nitrogen-containing Spiro ring (e.g., 1-    oxa-7-azaspiro[3.5]nonane), or-   (4) a 6-to 9-membered nitrogen-containing bridged ring (e.g.,    2-oxa-5-azabicyclo[4.1.0]heptane),-   each optionally further substituted by 1 to 3 substituents selected    from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a hydroxy group,    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (f) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl).

R¹ and R² are still more preferably each independently

-   (1) a hydrogen atom,-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl) optionally    substituted by 1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy).    -   (e) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl)        optionally substituted by 1 to 3 cyano groups, and    -   (f) an oxetanyl group,-   (3) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl) optionally    substituted by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl) optionally    substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),-   (4) a tetrahydrofuryl group, or-   (5) a tetrahydropyranyl group, or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom,-   (1) a morpholine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group, and    -   (c) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom),-   (2) a pyrrolidine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a hydroxy group, and    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 halogen atoms (e.g., a fluorine atom),-   (3) a piperidine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy),-   (4) an azetidine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a hydroxy group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl),    -   (d) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (e) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl),-   (5) an oxazepane ring (preferably 1,4-oxazepane) optionally further    substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),-   (6) a 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine ring,-   (7) a 1-oxa-7-azaspiro[3.5]nonane ring, or-   (8) a 2-oxa-5-azabicyclo[4.1.0]heptane ring.

R¹ and R² are even more preferably each independently

-   (1) a hydrogen atom,-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted    by 1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (d) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl) optionally        substituted by 1 to 3 cyano groups,-   (3) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl),-   (4) a tetrahydrofuryl group, or-   (5) a tetrahydropyranyl group, or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom,-   (1) a morpholine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom),-   (2) a pyrrolidine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a cyano group,    -   (b) a hydroxy group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (d) a C₁₋₆ alkoxy group (e.g., methoxy),-   (3) a piperidine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy),-   (4) an azetidine ring optionally further substituted by 1 to 3    halogen atoms (e.g., a fluorine atom),-   (5) an oxazepane ring (preferably 1,4-oxazepane) optionally further    substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),-   (6) a 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine ring, or-   (7) a 2-oxa-5-azabicyclo[4.1.0]heptane ring.

Even more preferably, R¹ is a hydrogen atom, and R² is atetrahydropyranyl group, or

-   R¹ and R² are bonded to each other to form, together with the 35    adjacent nitrogen atom,-   (1) a morpholine ring optionally further substituted by 1 to 3    (preferably 1) C₁₋₆ alkyl groups, or-   (2) a pyrrolidine ring optionally further substituted by 1 to 3    (preferably 1) cyano groups.

Particularly preferably, R¹ and R² are bonded to each other to form,together with the adjacent nitrogen atom,

-   (1) a morpholine ring optionally further substituted by one C₁₋₆    alkyl group (e.g., methyl), or-   (2) a pyrrolidine ring optionally further substituted by one cyano    group.

As another embodiment, particularly preferably,

-   R¹ is a hydrogen atom, and-   R² is a tetrahydropyranyl group, or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom, a morpholine ring optionally further    substituted by one C₁₋₆ alkyl group (e.g., methyl).

R³, R⁴, R⁵ and R⁶ are each independently a hydrogen atom, a halogenatom, an optionally substituted C₁₋₆ alkyl group or an optionallysubstituted C₁₋₆ alkoxy group.

The “C₁₋₆ alkyl group” of the “optionally substituted C₁₋₆ alkyl group”represented by R³, R⁴, R⁵ or R⁶ is optionally further substituted, atsubstitutable position(s), by substituent(s) selected from theabove-mentioned Substituent Group A. The number of the substituents is,for example, 1 to 3. When the number of the substituents is 2 or more,the respective substituents may be the same or different.

The “C₁₋₆ alkoxy group” of the “optionally substituted C₁₋₆ alkoxygroup” represented by R³, R⁴, R⁵ or R⁶ is optionally substituted, atsubstitutable position(s), by substituent(s) selected from theabove-mentioned Substituent Group A. The number of the substituents is,for example, 1 to 3. When the number of the substituents is 2 or more,the respective substituents may be the same or different.

R³ is preferably

-   (1) a hydrogen atom,-   (2) a halogen atom (e.g., a chlorine atom, a bromine atom), or-   (3) an optionally substituted C₁₋₆ alkyl group (e.g., methyl).

R³ is more preferably

-   (1) a hydrogen atom,-   (2) a halogen atom (e.g., a chlorine atom, a bromine atom), or-   (3) a C₁₋₆ alkyl group (e.g., methyl).

R³ is further more preferably

-   (1) a hydrogen atom,-   (2) a halogen atom (e.g., a bromine atom), or-   (3) a C₁₋₃ alkyl group (e.g., methyl).

R³ is particularly preferably

-   (1) a halogen atom (e.g., a bromine atom), or-   (2) a C₁₋₃ alkyl group (e.g., methyl).

R⁴ is preferably a hydrogen atom.

R⁵ is preferably a hydrogen atom.

R⁶ is preferably a hydrogen atom.

X is CR⁴ or N.

X is preferably CH or N.

X is particularly preferably CH.

Ring A is a 6-membered aromatic ring optionally further substituted by 1to 4 substituents selected from (i) a halogen atom, (ii) a C₁₋₆ alkylgroup and (iii) a C₁₋₆ alkoxy group.

Examples of the “6-membered aromatic ring” include a benzene ring, apyridine ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring anda triazine ring. The “6-membered aromatic ring” is preferably a benzenering.

Ring A is preferably a 6-membered aromatic ring (e.g., benzene)optionally further substituted by 1 to 4 (preferably 1 or 2) halogenatoms (e.g., a fluorine atom).

Ring A is more preferably a benzene ring optionally further substitutedby 1 or 2 halogen atoms (e.g., a fluorine atom).

Ring A is particularly preferably a benzene ring.

As another embodiment, Ring A is preferably a benzene ring optionallyfurther substituted by 1 to 4 (preferably 1) substituents selected from(i) a halogen atom (e.g., a fluorine atom), (ii) a C₁₋₆ alkyl group and(iii) a C₁₋₆ alkoxy group.

Preferable examples of compound (I) include the following compounds:

[Compound A]

Compound (I) wherein

-   R¹ and R² are each independently-   (1) a hydrogen atom,-   (2) an optionally substituted C₁₋₆ alkyl group (e.g., methyl, ethyl,    propyl),-   (3) an optionally substituted C₃₋₁₀ cycloalkyl group (e.g.,    cyclopropyl), or-   (4) an optionally substituted 3-to 14-membered non-aromatic    heterocyclic group (preferably a 3-to 8-membered monocyclic    non-aromatic heterocyclic group (e.g., tetrahydrofuryl,    tetrahydropyranyl)), or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom, an optionally further substituted 3-to    14-membered non-aromatic nitrogen-containing heterocycle (preferably    a 3-to 8-membered monocyclic non-aromatic nitrogen-containing    heterocycle (e.g., azetidine, pyrrolidine, piperidine, morpholine,    oxazepane (e.g., 1,4-oxazepane)), a 9-to 14-membered fused    polycyclic (preferably bi- or tri-cyclic) non-aromatic    nitrogen-containing heterocycle (e.g.,    2,3-dihydro-1H-pyrrolo[2,3-b]pyridine), a 6-to 9-membered    nitrogen-containing Spiro ring (e.g., 1-oxa-7-azaspiro[3.5]nonane),    a 6-to 9-membered nitrogen-containing bridged ring (e.g.,    2-oxa-5-azabicyclo[4.1.0]heptane));

R³ is

-   (1) a hydrogen atom,-   (2) a halogen atom (e.g., a chlorine atom, a bromine atom), or-   (3) an optionally substituted Ci-o alkyl group (e.g., methyl);-   X is CH or N;-   R⁵ is a hydrogen atom;-   R⁶ is a hydrogen atom; and-   Ring A is a 6-membered aromatic ring (e.g., benzene) optionally    further substituted by 1 to 4 (preferably 1 or 2) halogen atoms    (e.g., a fluorine atom).

[Compound B]

Compound (I) wherein

-   R¹ and R² are each independently-   (1) a hydrogen atom,-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl) optionally    substituted by 1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),    -   (e) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl)        optionally substituted by 1 to 3 cyano groups, and    -   (f) a 3-to 14-membered non-aromatic heterocyclic group        (preferably a 3-to 8-membered monocyclic non-aromatic        heterocyclic group (e.g., oxetanyl)),-   (3) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl) optionally    substituted by 1 to 3₁₋₆ alkyl groups (e.g., methyl) optionally    substituted by 1 to 3 halogen atoms (e.g., a 35 fluorine atom), or-   (4) a 3-to 14-membered non-aromatic heterocyclic group (preferably a    3-to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,    tetrahydrofuryl, tetrahydropyranyl)), or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom, a 3-to 14-membered non-aromatic    nitrogen-containing heterocycle (preferably a 3-to 8-membered    monocyclic non-aromatic nitrogen-containing heterocycle (e.g.,    azetidine, pyrrolidine, piperidine, morpholine, oxazepane (e.g.,    1,4-oxazepane)), a 9-to 14-membered fused polycyclic (preferably bi-    or tri-cyclic) non-aromatic nitrogen-containing heterocycle (e.g.,    2,3-dihydro-1H-pyrrolo[2,3-b]pyridine), a 6-to 9-membered    nitrogen-containing spiro ring (e.g., 1-oxa-7-azaspiro[3.5]nonane),    a 6-to 9-membered nitrogen-containing bridged ring (e.g.,    2-oxa-5-azabicyclo[4.1.0]heptane)) optionally further substituted by    1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a hydroxy group,    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (f) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl);-   R³ is    -   (1) a hydrogen atom,-   (2) a halogen atom (e.g., a chlorine atom, a bromine atom), or-   (3) a C₁₋₆ alkyl group (e.g., methyl);-   X is CH or N;-   R⁵ is a hydrogen atom;-   R⁶ is a hydrogen atom; and-   Ring A is a benzene ring optionally further substituted by 1 or 2    halogen atoms (e.g., a fluorine atom).

[Compound C]

[Compound B] wherein

-   R¹ and R² are each independently-   (1) a hydrogen atom,-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl) optionally    substituted by 1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),    -   (e) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl) is        optionally substituted by 1 to 3 cyano groups, and    -   (f) a 3-to 8-membered monocyclic non-aromatic heterocyclic group        (e.g., oxetanyl),-   (3) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl) optionally    substituted by 1 to 3 0₁-₆ alkyl groups (e.g., methyl) optionally    substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), or-   (4) a 3-to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., tetrahydrofuryl, tetrahydropyranyl), or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom,-   (1) a 3-to 8-membered monocyclic non-aromatic nitrogen-containing    heterocycle (e.g., azetidine, pyrrolidine, piperidine, morpholine,    oxazepane (e.g., 1,4-oxazepane)),-   (2) a 9-to 14-membered fused bi- or tri-cyclic non-aromatic    nitrogen-containing heterocycle (e.g.,    2,3-dihydro-1H-pyrrolo[2,3-b]pyridine),-   (3) a 6-to 9-membered nitrogen-containing spiro ring (e.g.,    1-oxa-7-azaspiro[3.5]nonane), or-   (4) a 6-to 9-membered nitrogen-containing bridged ring (e.g.,    2-oxa-5-azabicyclo[4.1.0]heptane), each optionally further    substituted by 1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a hydroxy group,    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (f) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl).

[Compound D]

[Compound B] wherein

-   R¹ and R² are each independently-   (1) a hydrogen atom,-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl) optionally    substituted by 1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),    -   (e) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl)        optionally substituted by 1 to 3 cyano groups, and    -   (f) an oxetanyl group,-   (3) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl) optionally    substituted by 1 to 3 C₁₋₆ alkyl groups (e.g., methyl) optionally    substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),-   (4) a tetrahydrofuryl group, or-   (5) a tetrahydropyranyl group, or R¹ and R² are bonded to each other    to form, together with the 35 adjacent nitrogen atom,-   (01) a morpholine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group, and    -   (c) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom),-   (2) a pyrrolidine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 substituents selected from        -   (i) a halogen atom (e.g., a fluorine atom), and        -   (ii) a hydroxy group, and    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy) optionally substituted        by 1 to 3 halogen atoms (e.g., a fluorine atom),-   (3) a piperidine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),        and5    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy),-   (4) an azetidine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a hydroxy group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl),    -   (d) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (e) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl),-   (5) an oxazepane ring (preferably 1,4-oxazepane) optionally further    substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),-   (6) a 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine ring,-   (7) a 1-oxa-7-azaspiro[3.5]nonane ring, or-   (8) a 2-oxa-5-azabicyclo[4.1.0]heptane ring.

[Compound E]

[Compound B] wherein

-   R¹ and R² are each independently-   (1) a hydrogen atom,-   (2) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally substituted    by 1 to 3 substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a C₁₋₆ alkoxy group (e.g., methoxy), and    -   (d) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl) optionally        substituted by 1 to 3 cyano groups,-   (3) a C₃₋₆ cycloalkyl group (e.g., cyclopropyl),-   (4) a tetrahydrofuryl group, or-   (5) a tetrahydropyranyl group, or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom,-   (1) a morpholine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom), and    -   (b) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom),-   (2) a pyrrolidine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a cyano group,    -   (b) a hydroxy group,    -   (c) a C₁₋₆ alkyl group (e.g., methyl) optionally substituted by        1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (d) a C₁₋₆ alkoxy group (e.g., methoxy),-   (3) a piperidine ring optionally further substituted by 1 to 3    substituents selected from    -   (a) a halogen atom (e.g., a fluorine atom),    -   (b) a cyano group,    -   (c) a hydroxy group,    -   (d) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and    -   (e) a C₁₋₆ alkoxy group (e.g., methoxy),-   (4) an azetidine ring optionally further substituted by 1 to 3    halogen atoms (e.g., a fluorine atom),-   (5) an oxazepane ring (preferably 1,4-oxazepane) optionally further    substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),-   (6) a 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine ring, or-   (7) a 2-oxa-5-azabicyclo[4.1.0]heptane ring; and-   X is CH.

[Compound F]

Compound (I) wherein

-   R¹ is a hydrogen atom, and-   R² is a tetrahydropyranyl group, or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom,-   (1) a morpholine ring optionally further substituted by 1 to 3    (preferably 1) C₁₋₆ alkyl groups, or-   (2) a pyrrolidine ring optionally further substituted by 1 to 3    (preferably 1) cyano groups;-   R³ is-   (1) a hydrogen atom,-   (2) a halogen atom (e.g., a bromine atom), or-   (3) a C₁₋₃ alkyl group (e.g., methyl);-   X is CH;-   R⁵ is a hydrogen atom;-   R⁶ is a hydrogen atom; and-   Ring A is a benzene ring.

[Compound G]

[Compound F] wherein

-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom,-   (1) a morpholine ring optionally further substituted by one C₁₋₆    alkyl group (e.g., methyl), or-   (2) a pyrrolidine ring optionally further substituted by one cyano    group; and-   R³ is-   (1) a halogen atom (e.g., a bromine atom), or-   (2) a C₁₋₃ alkyl group (e.g., methyl).

[Compound H]

[Compound F] wherein

R¹ is a hydrogen atom, and

-   R² is a tetrahydropyranyl group, or-   R¹ and R² are bonded to each other to form, together with the    adjacent nitrogen atom, a morpholine ring optionally further    substituted by one C₁₋₆ alkyl group (e.g., methyl); and-   R³ is-   (1) a halogen atom (e.g., a bromine atom), or-   (2) a C₁₋₃ alkyl group (e.g., methyl).

[Compound I]

-   3-bromo-9-(4-(morpholin-4-ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one,    or a salt thereof.-   3-bromo-9-(4-M2S)-2-methylmorpholin-4-yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one,    or a salt thereof.-   4-(3-methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3S)-tetrahydro-2H-pyran-3-yl)benzamide,    or a salt thereof.

Specific examples of compound (I) include the compounds of Examples 1 to133.

When compound (I) is a salt, it is preferably a 5 pharmacologicallyacceptable salt, and examples of such salt include a salt with inorganicbase, a salt with organic base, a salt with inorganic acid, a salt withorganic acid, a salt with basic or acidic amino acid and the like.

Preferable examples of the salt with inorganic base include alkali metalsalts such as sodium salt, potassium salt and the like, alkaline earthmetal salts such as calcium salt, magnesium salt and the like, aluminumsalt, ammonium salt and the like.

Preferable examples of the salt with organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine,tromethamine[tris(hydroxymethyl)methylamine], tert-butylamine,cyclohexylamine, benzylamine, dicyclohexylamine,N,N-dibenzylethylenediamine and the like.

Preferable examples of the salt with inorganic acid include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like.

Preferable examples of the salt with organic acid include salts withformic acid, acetic acid, trifluoroacetic acid, 25 phthalic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like.

Preferable examples of the salt with basic amino acid include salts witharginine, lysine, ornithine and the like. Preferable examples of thesalt with acidic amino acid include salts with aspartic acid, glutamicacid and the like.

The production method of the compound of the present invention isexplained below.

The raw material compound and reagent used and the compound obtained ineach step in the following production method may be each in a form of asalt, and examples of such salt include those similar to the salts ofcompound (I) and the like.

When the compound obtained in each step is a free form, it can beconverted to the objective salt according to a method lo known per se.When the compound obtained in each step is a salt, it can be convertedto the objective free form or the other salt according to a method knownper se.

The compound obtained in each step can be used directly as the reactionmixture or as a crude product for the next reaction. Alternatively, thecompound obtained in each step can be isolated and purified from areaction mixture according to a method known per se, for example, aseparation means such as concentration, crystallization,recrystallization, distillation, solvent extraction, fractionaldistillation, column chromatography and the like.

When the raw material compound and reagent used in each step arecommercially available, the commercially available product can also beused directly.

In the reaction in each step, while the reaction time varies dependingon the kind of the reagent and solvent to be used, it is generally 1min-48 hr, preferably 10 min-8 hr, unless otherwise specified.

In the reaction in each step, while the reaction temperature variesdepending on the kind of the reagent and solvent to be used, it isgenerally -78° C.-300° C., preferably −78° C.-150° C., unless otherwisespecified.

In the reaction in each step, while the pressure varies depending on thekind of the reagent and solvent to be used, it is generally 1 atm-20atm, preferably 1 atm-3 atm, unless otherwise specified.

Microwave synthesizer such as Initiator manufactured by Biotage and thelike may be used for the reaction in each step. While the reactiontemperature varies depending on the kind of the reagent and solvent tobe used, it is generally room temperature-300° C., preferably 50°C.-250° C., unless otherwise specified. While the reaction time variesdepending on the kind of the reagent and solvent to be used, it isgenerally 1 min-48 hr, preferably 1 min-8 hr, unless otherwisespecified.

In the reaction in each step, the reagent is used in an amount of 0.5equivalents-20 equivalents, preferably 0.8 equivalents-5 equivalents,relative to the substrate, unless otherwise specified. When the reagentis used as a catalyst, the reagent is used in an amount of 0.001equivalent-1 equivalent, preferably 0.01 equivalent-0.2 equivalent,relative to the substrate. When the reagent is used as a reactionsolvent, the reagent is used in a solvent amount.

Unless otherwise specified, the reaction in each step is carried outwithout solvent, or by dissolving or suspending the raw materialcompound in a suitable solvent. Examples of the solvent include thosedescribed in Examples and the following solvents.

alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol,2-methyl-2-butanol and the like; ethers: diethyl ether, diphenyl ether,tetrahydrofuran, 1,2-dimethoxyethane and the like;

aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;

-   saturated hydrocarbons: cyclohexane, hexane and the like; amides:    N,N-dimethylformamide, N-methylpyrrolidone and the li0ke;

halogenated hydrocarbons: dichloromethane, carbon tetrachloride and thelike;

-   nitriles: acetonitrile and the like;-   sulfoxides: dimethyl sulfoxide and the like;-   aromatic organic bases: pyridine and the like;-   anhydrides: acetic anhydride and the like;-   organic acids: formic acid, acetic acid, trifluoroacetic acid and    the like;-   inorganic acids: hydrochloric acid, sulfuric acid and the like;-   esters: ethyl acetate and the like;-   ketones: acetone, methyl ethyl ketone and the like; water.

The above-mentioned solvent can be used in a mixture of two or morekinds thereof in an appropriate ratio.

When a base is used for the reaction in each step, examples thereofinclude those described in Examples and the following bases.

-   inorganic bases: sodium hydroxide, magnesium hydroxide, sodium    carbonate, calcium carbonate, sodium hydrogen carbonate and the    like;-   organic bases: triethylamine, diethylamine, pyridine,    4-dimethylaminopyridine, N,N-dimethylaniline,    1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,    imidazole, piperidine, N,N-diisopropylethylamine and the like;-   metal alkoxides: sodium ethoxide, potassium tert-butoxide and the    like;-   alkali metal hydrides: sodium hydride and the like;-   metal amides: sodium amide, lithium diisopropylamide, lithium    hexamethyldisilazide and the like;-   organic lithiums: n-butyllithium and the like.

When an acid or an acid catalyst is used for the reaction in each step,examples thereof include those described in Examples and the followingacids and acid catalysts. inorganic acids: hydrochloric acid, sulfuricacid, nitric acid, hydrobromic acid, phosphoric acid and the like;organic acids: acetic acid, trifluoroacetic acid, citric acid,p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; Lewisacid: boron trifluoride diethyl ether complex, zinc iodide, anhydrousaluminum chloride, anhydrous zinc chloride, anhydrous iron chloride andthe like.

Unless otherwise specified, the reaction in each step is carried outaccording to a method known per se, for example, the method described inJikken Kagaku Kouza, 5th Edition, vol.13-19 (the Chemical Society ofJapan ed.); Shin Jikken Kagaku Kouza, vol.14-15 (the Chemical Society ofJapan ed.); Fine Organic Chemistry, Revised 2nd Edition (L. F. Tietze,Th. Eicher, Nankodo); Organic Name Reactions, the Reaction Mechanism andEssence, Revised Edition (Hideo Togo, Kodansha); ORGANIC SYNTHESESCollective Volume I-VII (John Wiley & Sons Inc.); Modern OrganicSynthesis in the Laboratory A Collection of Standard ExperimentalProcedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive HeterocyclicChemistry III, Vol. 1-Vol. 14 (Elsevier Japan); Strategic Applicationsof Named Reactions in Organic Synthesis (translated by Kiyoshi Tomioka,Kagakudojin); Comprehensive Organic Transformations (VCH PublishersInc.), 1989, or the like, or the method described in Examples.

In each step, the protection or deprotection reaction of an functionalgroup is carried out according to a method known per se, for example,the method described in “Protective Groups in Organic Synthesis, 4thEd”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M.Wuts); “Protecting Groups 3rd Ed.” Thieme, 2004 (P. J. Kocienski), orthe like, or the method described in Examples.

Examples of the protecting group for a hydroxy group of an alcohol andthe like and a phenolic hydroxy group include ether-type protectinggroups such as methoxymethyl ether, benzyl ether,tert-butyldimethylsilyl ether, tetrahydropyranyl ether and the like;carboxylate ester-type protecting groups such as acetate ester and thelike; sulfonate ester-type protecting groups such as methanesulfonateester and the like; carbonate ester-type protecting groups such astert-butylcarbonate and the like, and the like.

Examples of the protecting group for a carbonyl group of an aldehydeinclude acetal-type protecting groups such as dimethylacetal and thelike; cyclic acetal-type protecting groups such as 1,3-dioxane and thelike, and the like.

Examples of the protecting group for a carbonyl group of a ketoneinclude ketal-type protecting groups such as dimethylketal and the like;cyclic ketal-type protecting groups such as 1,3-dioxane and the like;oxime-type protecting groups such as O-methyloxime and the like;hydrazone-type protecting groups such as N,N-dimethylhydrazone and thelike, and the like.

Examples of the protecting group for a carboxyl group include ester-typeprotecting groups such as methyl ester and the like; amide-typeprotecting groups such as N,N-dimethylamide and the like, and the like.

Examples of the protecting group for a thiol include ether-typeprotecting groups such as benzyl thioether and the like; ester-typeprotecting groups such as thioacetate ester, thiocarbonate,thiocarbamate and the like, and the like.

Examples of the protecting group for an amino group and an aromaticheterocycle such as imidazole, pyrrole, indole and the like includecarbamate-type protecting groups such as benzyl carbamate and the like;amide-type protecting groups such as acetamide and the like; alkylamine-type protecting groups such as N-triphenylmethylamine and thelike; sulfonamide-type protecting groups such as methanesulfonamide andthe like, and the like.

The protecting groups can be removed according to a method known per se,for example, by employing a method using acid, base, ultraviolet rays,hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide(e.g., trimethylsilyl iodide, trimethylsilyl bromide) and the like, areduction method, and the like.

When reduction reaction is carried out in each step, examples of thereducing agent to be used include metal hydrides such as lithiumaluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride,diisobutylaluminum hydride (DIBAL-H), sodium borohydride,tetramethylammonium triacetoxyborohydride and the like; boranes such asborane tetrahydrofuran complex and the like; Raney nickel; Raney cobalt;hydrogen; formic acid; triethylsilane and the like. When carbon-carbondouble bond or triple bond is reduced, a method using a catalyst such aspalladium-carbon, Lindlar's catalyst and the like may be employed.

When oxidation reaction is carried out in each step, examples of theoxidizing agent to be used include peroxides such as m-chloroperbenzoicacid (mCPBA), hydrogen peroxide, tert-butylhydroperoxide and the like;perchlorates such as tetrabutylammonium perchlorate and the like;chlorates such as sodium chlorate and the like; chlorites such as sodiumchlorite and the like; periodates such as sodium periodate and the like;hypervalent iodine reagents such as iodosylbenzene and the like;reagents containing manganese such as manganese dioxide, potassiumpermanganate and the like; leads such as lead tetraacetate and the like;reagents containing chromium such as pyridinium chlorochromate (PCC),pyridinium dichromate (PDC), Jones reagent and the like; halogencompounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone;sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide;2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

When radical cyclization reaction is carried out in each step, examplesof the radical initiator to be used include azo compounds such asazobisisobutyronitrile (AIBN) and the like; water-soluble radicalinitiators such as 4-4′-azobis-4-cyanopentanoic acid (ACPA) and thelike; triethylboron in the presence of air or oxygen; benzoyl peroxideand the like. Examples of the radical reagent to be used includetributylstannane, tristrimethylsilylsilane, tetraphenyldisilane,diphenylsilane, samarium iodide and the like.

When Wittig reaction is carried out in each step, examples of the Wittigreagent to be used include alkylidene phosphoranes and the like. Thealkylidene phosphoranes can be prepared according to a method known perse, for example, by reacting a phosphonium salt with a strong base.

When Horner-Emmons reaction is carried out in each step, examples of thereagent to be used include phosphonoacetates such as methyldimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like;and bases such as alkali metal hydrides, organic lithiums and the like.

When Friedel-Crafts reaction is carried out in each step, a combinationof a Lewis acid and an acid chloride or a combination of a Lewis acidand an alkylating agent (e.g., an alkyl halide, an alcohol, an olefinetc.) is used as a reagent. Alternatively, an organic acid or aninorganic acid can also be used instead of a Lewis acid, and ananhydride such as acetic anhydride and the like can also be used insteadof an acid chloride.

When aromatic nucleophilic substitution reaction is carried out in eachstep, a nucleophile (e.g., an amine, imidazole etc.) and a base (e.g.,an organic base etc.) are used as a reagent.

When nucleophilic addition reaction by a carbo anion, nucleophilic1,4-addition reaction (Michael addition reaction) by a carbo anion ornucleophilic substitution reaction by a carbo anion is carried out ineach step, and examples of the base to be used for generation of thecarbo anion include organic lithiums, metal alkoxides, inorganic bases,organic bases and the like.

When Grignard reaction is carried out in each step, examples of theGrignard reagent to be used include arylmagnesium halides such asphenylmagnesium bromide and the like; and alkylmagnesium halides such asmethylmagnesium bromide and the like. The Grignard reagent can beprepared according to a method known per se, for example, by reacting analkyl halide or an aryl halide with a metal magnesium in an ether ortetrahydrofuran as a solvent.

When Knoevenagel condensation reaction is carried out in each step, acompound having an activated methylene group with two electronwithdrawing groups (e.g., malonic acid, diethyl malonate, malononitrileetc.) and a base (e.g., an organic reagent.

When Vilsmeier-Haack reaction is carried out in each step, phosphorylchloride and an amide derivative (e.g., N,N-dimethylformamide etc.) areused as a reagent.

When azidation reaction of an alcohol, an alkyl halide or a sulfonate iscarried out in each step, examples of the azidating agent to be usedinclude diphenylphosphorylazide (DPPA), trimethylsilylazide, sodiumazide and the like. For example, for the azidation reaction of analcohol, a method using diphenylphosphorylazide and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a method usingtrimethylsilylazide and a Lewis acid, and the like are employed.

When reductive amination reaction is carried out in each step, examplesof the reducing agent to be used include sodium triacetoxyborohydride,sodium cyanoborohydride, hydrogen, formic acid and the like. When thesubstrate is an amine compound, examples of the carbonyl compound to beused include paraformaldehyde, aldehydes such as acetaldehyde and thelike, and ketones such as cyclohexanone and the like. When the substrateis a carbonyl compound, examples of the amine to be used includeammonia, primary amines such as methylamine and the like; secondaryamines such as dimethylamine and the like, and the like.

When Mitsunobu reaction is carried out in each step, an azodicarboxylate(e.g., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate(DIAD) etc.) and triphenylphosphine are used as a reagent.

When esterification reaction, amidation reaction or urea formationreaction is carried out in each step, examples of the reagent to be usedinclude acyl halides such as acid chlorides, acid bromides and the like;activated carboxylic acids such as anhydrides, activated esters,sulfates and the like. Examples of the activating agent of thecarboxylic acid include carbodiimide condensing agents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) hydrochloride andthe like; triazine condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloriden-hydrate (DMT-MM) and the like; carbonate condensing agents such as1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide(DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOPreagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent);thionyl chloride; lower alkyl haloformates such as ethyl chloroformateand the like; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphorate (HATU); sulfuric acid; combinations thereof andthe like. When carbodiimide condensing agent is used, an additive suchas 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DHAP) and the like may be added to the reactionsystem.

When coupling reaction is carried out in each step, examples of themetal catalyst to be used include palladium compounds such aspalladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride and thelike; nickel compounds such as tetrakis(triphenylphosphine)nickel(0) andthe like; rhodium compounds such as tris(triphenylphosphine)rhodium(III)chloride and the like; cobalt compounds; copper compounds such as copperoxide, copper(I) iodide and the like; platinum compounds and the like.In addition, a base can be added to the reaction system, and examplesthereof include inorganic bases and the like.

When thiocarbonylation reaction is carried out in each step, phosphoruspentasulfide is typically used as the thiocarbonylating agent.Alternatively, a reagent having a1,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g.,2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson reagent) etc.) can also be used instead of phosphoruspentasulfide.

When Wohl-Ziegler reaction is carried out in each step, examples of thehalogenating agent to be used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfurylchloride and the like. In addition, the reaction can be accelerated bysubjecting a radical initiator such as heat, light, benzoyl peroxide,azobisisobutyronitrile and the like to the reaction system reaction.

When halogenation reaction of a hydroxy group is carried out in eachstep, examples of the halogenating agent to be used include hydrohalicacids and acid halides of inorganic acids, specifically, hydrochloricacid, thionyl chloride, phosphorus oxychloride and the like forchlorination, 48% hydrobromic acid and the like for bromination. Inaddition, a method of producing an alkyl halide by reacting an alcoholwith triphenylphosphine and carbon tetrachloride or carbon tetrabromideor the like can be employed. Alternatively, a method of producing analkyl halide via two steps comprising converting an alcohol to thecorresponding sulfonate, and then reacting the sulfonate with lithiumbromide, lithium chloride or sodium iodide can also be employed.

When Arbuzov reaction is carried out in each step, examples of thereagent to be used include alkyl halides such as ethyl bromoacetate andthe like; and phosphites such as triethyl phosphite, tri(isopropyl)phosphite and the like.

When sulfonate esterification reaction is carried out in each step,examples of the sulfonating agent to be used include methanesulfonylchloride, p-toluenesulfonyl chloride, methanesulfonic anhydride,p-toluenesulfonic anhydride and the like.

When hydrolysis reaction is carried out in each step, an acid or a baseis used as a reagent. For acid hydrolysis reaction of tert-butyl ester,formic acid, triethylsilane and the like may be added toreductively-trap tert-butyl cation which is by-produced.

When dehydration reaction is carried out in each step, examples of thedehydrating agent to be used include sulfuric acid, diphosphoruspentaoxide, phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide,alumina, polyphosphoric acid and the like.

Compound (I-1), which is compound (I) wherein R³ is a hydrogen atom, anoptionally substituted C₁₋₆ alkyl group or an optionally substitutedC₁₋₆ alkoxy group, can be produced from compound (1) according to thefollowing method.

wherein Hal is a halogen atom, R⁷ is a hydrogen atom, an optionallysubstituted C₁₋₆ alkyl group or an optionally substituted C₁₋₆ alkoxygroup, R is an optionally substituted C₁₋₆ alkyl group, R′ is a C₁₋₆alkyl group, and Y is a boronic acid group (—B(OH)₂), a boronate estergroup (—B(OR″)₂, a trifluoroborate group; R″ is a C₁₋₆ alkyl group) or acyclic group thereof (e.g., 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, etc.), and the other symbols are as defined above.

Examples of the “optionally substituted C₁₋₆ alkyl group” and“optionally substituted C₁₋₆ alkoxy group” represented by R⁷ includethose exemplified as the above-mentioned R³ and the like.

Examples of the “optionally substituted C₁₋₆ alkyl group” represented byR include those exemplified as the above-mentioned R³ and the like.4

Compound (I-1) can be produced by subjecting compound (2) to theSuzuki-Miyaura coupling reaction with compound (9).

Compound (I-1) can also be produced by subjecting compound (5) to anamidation reaction.

Compound (2) can be produced by subjecting compound (1) to a cyclizationreaction with compound (8).

Compound (5) can be produced by subjecting compound (4) to a hydrolysisreaction.

Compound (4) can be produced by subjecting compound (3) to a cyclizationreaction with compound (8).

Compound (4) can also be produced by subjecting compound (2) to theSuzuki-Miyaura coupling reaction with compound (10).

Compound (4) can also be produced by subjecting compound (2) to aborylation reaction, followed by the Suzuki-Miyaura coupling reactionwith compound (11). The borylation reaction of compound (2) can becarried out by reacting compound (2) with a borylating reagent in thepresence of a palladium catalyst and a base. Examples of the borylatingreagent include bispinacolatodiborane and the like.

Compound (3) can be produced by subjecting compound (1) to theSuzuki-Miyaura coupling reaction with compound (10).

Compound (I-2), which is compound (I) wherein R³ is a halogen atom, canbe produced from compound (I-1-1), which is compound (I-1) wherein R⁷ isa hydrogen atom, according to the following method.

wherein R⁸ is a halogen atom, and the other symbols are as definedabove.

Compound (I-2) can be produced by subjecting compound (I-1-1) to ahalogenation reaction.

Compound (I-2) can also be produced from compound (4-1), which iscompound (4) wherein R⁷ is a hydrogen atom, according to the followingmethod.

wherein each symbol is as defined above.

Compound (1-2) can be produced by subjecting compound (6) to anamidation reaction.

Compound (6) can be produced by subjecting compound (7) to a hydrolysisreaction.

Compound (7) can be produced by subjecting compound (4-1) to ahalogenation reaction.

Compound (6) can be produced from compound (5-1), which is compound (5)wherein R⁷ is a hydrogen atom, according to the following method.

wherein each symbol is as defined above.

Compound (6) can be produced by subjecting compound (5-1) to ahalogenation reaction.

Compound (9) can be produced from compound (12) according to thefollowing method.

wherein each symbol is as defined above.

Compound (9) can be produced by subjecting compound (13) to a borylationreaction. The borylation reaction of compound (13) can be carried out byreacting compound (13) with a borylating reagent, in the presence of apalladium catalyst and a base. Examples of the borylating reagentinclude bispinacolatodiborane and the like.

Compound (13) can be produced by subjecting compound (12) to anamidation reaction.

Compound (10) can be produced from compound (11) according to thefollowing method.

wherein each symbol is as defined above.

Compound (10) can be produced by subjecting compound (11) to aborylation reaction. The borylation reaction of compound (11) can becarried out by reacting compound (11) with a borylating reagent, in thepresence of a palladium catalyst and a base. Examples of the borylatingreagent include bispinacolatodiborane and the like.

Where necessary, in any of the above-mentioned reaction schemes, R¹-R⁸,Hal, R and R′ can also be converted by using a general organic reactionsingly or using a plurality of general organic reactions in combination,for example, halogenation reaction, acylation reaction, sulfonylationreaction, alkylation reaction, hydrolysis reaction, amination reaction,amidation reaction, esterification reaction, etherification reaction,oxidation reaction, reduction reaction, protection reaction,deprotection reaction, coupling reaction, addition reaction, eliminationreaction, substitution reaction and the like.

Compound (1), compound (8), compound (11) and compound (12) may beavailable commercially product, or can also be produced by a methodknown per se, or a method analogous thereto.

In the thus-obtained compound (I), an intramolecular functional groupcan also be converted to an object functional group by a combination ofchemical reactions known per se. Examples of the chemical reactioninclude oxidation reaction, reduction reaction, alkylation reaction,acylation reaction, ureation reaction, hydrolysis reaction, aminationreaction, esterification reaction, aryl coupling reaction, deprotectionreaction and the like.

In the above-mentioned production method, when a starting compound hasan amino group, a carboxyl group, a hydroxy group, a carbonyl group or amercapto group as a substituent, a protecting group generally used inthe peptide chemistry may be introduced into these groups, and theobject compound can be obtained by removing the protecting group asnecessary after the reaction.

Compound (I) obtained by the above-mentioned production method can beisolated and purified by a known means, such as solvent extraction,liquid conversion, phase transfer, crystallization, recrystallization,chromatography and the like.

When compound (I) contains an optical isomer, a stereoisomer, aregioisomer and a rotamer, these compounds are also encompassed incompound (I), and each can be obtained as a single product according toa synthesis method or separation method known per se. For example, whenan optical isomer exists in compound (I), the optical isomer resolvedfrom the compound is also encompassed in compound (I).

The optical isomer can be produced according to a method known per se.Specifically, the optical isomer is obtained using an optically activesynthetic intermediate or by subjecting the racemic final product to anoptical resolution according to a known method.

The optical resolution may be a method known per se, such as afractional recrystallization method, a chiral column method, adiastereomer method etc.

1) Fractional recrystallized method

A method wherein a salt of a racemate with an optically active compound(e.g., (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid,(−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine,cinchonine, (−)-cinchonidine, brucine etc.) is formed, which isseparated by a fractional recrystallized method, and if desired, aneutralization step to give a free optical isomer.

2) Chiral column method

A method wherein a racemate or a salt thereof is applied to a column (achiral column) for separation of an optical isomer to allow separation.In the case of a liquid chromatography, for example, a mixture of theoptical isomers is applied to a chiral column such as ENANTIO-OVM(manufactured by Tosoh Corporation), CHIRAL series (manufactured byDaicel Chemical Industries, Ltd.) and the like, and developed withwater, various buffers (e.g., phosphate buffer, etc.) and organicsolvents (e.g., ethanol, methanol, isopropanol, acetonitrile,trifluoroacetic acid, diethylamine, etc.) as an eluent, solely or inadmixture to separate the optical isomer.

3) Diastereomer method

A method wherein a racemic mixture is prepared into a diastereomericmixture by chemical reaction with an optically active reagent, which ismade into a single substance by a typical separation means (e.g., afractional recrystallized method, a chromatography method etc.) and thelike, and is subjected to a chemical treatment such as hydrolysis andthe like to separate an optically active reagent moiety, whereby anoptical isomer is obtained. For example, when compound (I) contains ahydroxy group or a primary or secondary amino group in a molecule, thecompound and an optically active organic acid (e.g., MTPA[α-methoxy-a-(trifluoromethyl)phenylacetic acid], (−)-menthoxyaceticacid etc.) and the like are subjected to condensation reaction to givediastereomers of the ester compound or the amide compound, respectively.When compound (I) has a carboxy group, the compound and an opticallyactive amine or an optically active alcohol reagent are subjected tocondensation reaction to give diastereomers of the amide compound or theester compound, respectively. The separated diastereomer is converted toan optical isomer of the original compound by acid hydrolysis or basehydrolysis.

Compound (I) may be a crystal. A single crystal form and a mixture ofcrystal forms are both encompassed in compound (I).

A crystal of compound (I) can be produced by crystallizing compound (I),by applying a crystallization method known per se.

In the present specification, the melting point means a melting pointmeasured, for example, by micro melting point apparatus (Yanako, MP-500Dor Buchi, B-545), DSC (differential scanning calorimetry analysis)apparatus (SEIKO, EXSTAR6000) and the like.

Generally, the melting point sometimes varies depending on themeasurement device, measurement condition and the like. The crystal ofcompound (I) may be a crystal showing a melting point different from thevalues described in the present specification as long as the differenceis within a general error range.

The crystal of compound (I) is superior in the physicochemicalproperties (e.g., melting point, solubility, stability) and biologicalproperties (e.g., pharmacokinetics (absorbability, distribution,metabolism, excretion), efficacy expression), and is extremely useful asa medicament.

Furthermore, compound (I) may be a pharmaceutically acceptable cocrystalor cocrystal salt. The cocrystal or cocrystal salt means a crystallinesubstance constituted with two or more special solids at roomtemperature, each having different physical properties (e.g., structure,melting point, melting heat, hygroscopicity, solubility and stability).The cocrystal or cocrystal salt can be produced by a cocrystallizationmethod known per se.

When compound (I) has an asymmetric center, isomers such as enantiomer,diastereomer and the like may be present. Such isomer and a mixturethereof are encompassed in the present invention. In addition, whenisomer due to conformation or tautomerism is present, such isomer and amixture thereof are also encompassed in compound (I) of the presentinvention.

Compound (I) may be used as a prodrug. A prodrug of compound (I) means acompound which is converted to compound (I) of the present inventionwith a reaction due to an enzyme, an gastric acid, etc. under thephysiological condition in the living body, that is, a compound which isconverted to compound (I) of the present invention with oxidation,reduction, hydrolysis, etc. according to an enzyme; a compound which isconverted to compound (I) of the present invention by hydrolysis etc.due to gastric acid, etc.

A prodrug of compound (I) may be a compound obtained by subjecting anamino group in compound (I) to an acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin compound (I) to an eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in compound (I) to an acylation, alkylation, phosphorylation orboration (e.g., a compound obtained by subjecting an hydroxy group incompound (I) to an acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, etc.); a compound obtained bysubjecting a carboxyl group in compound (I) to an esterification oramidation (e.g., a compound obtained by subjecting a carboxyl group incompound (I) to an ethyl esterification, phenyl esterification,carboxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification andmethylamidation, etc.) and the like. Any of these compounds can beproduced from compound (I) by a method known per se.

A prodrug for compound (I) may also be one which is converted intocompound (I) under a physiological condition, such as those described inIYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design ofMolecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).

In the present specification, a prodrug may form a salt, and examples ofsuch salt include those exemplified as a salt of compound (I).

Compound (I) may be labeled with an isotope (e.g., ³H, ¹³C, ¹⁴C, ¹⁸F,³⁵S, ¹²⁵I) and the like.

Compound (I) labeled with or substituted by an isotope can be used, forexample, as a tracer used for Positron Emission Tomography (PET) (PETtracer), and expected to be useful in the field of medical diagnosis andthe like.

Furthermore, compound (I) may be a hydrate or a non-hydrate, or anon-solvate (e.g., anhydride), or a solvate (e.g., hydrate).

Compound (I) also encompasses a deuterium conversion form wherein ¹H isconverted to ²H(D).

A medicament containing compound (I) (In the present specification,sometimes to be referred to as “the medicament of the presentinvention”) can be used solely or as a pharmaceutical compositionprepared by mixing with a pharmacologically acceptable carrier,according to a method known per se (e.g., the method described in theJapanese Pharmacopoeia etc.) as the production method of a

As the “pharmacologically acceptable carrier”, various organic orinorganic carrier substances conventionally used as preparationmaterials can be used. These are incorporated as excipient, lubricant,binder and disintegrant for solid preparations; or solvent, solubilizingagent, suspending agent, isotonicity agent, buffer and soothing agentfor liquid preparations; and the like; and preparation additives such aspreservative, antioxidant, colorant, sweetening agent and the like canbe used as necessary.

Preferable examples of the excipient include lactose, sucrose,D-mannitol, D-sorbitol, starch, gelatinated starch, dextrin, crystallinecellulose, low-substituted hydroxypropylcellulose, sodiumcarboxymethylcellulose, gum arabic, pullulan, light anhydrous silicicacid, synthetic aluminum silicate and magnesium alumino metasilicate.

Preferable examples of the lubricant include magnesium stearate, calciumstearate, talc and colloidal silica.

Preferable examples of the binder include gelatinated starch, sucrose,gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol,trehalose, dextrin, pullulan, hydroxypropylcellulose,hydroxypropylmethylcellulose and polyvinylpyrrolidone.

Preferable examples of the disintegrant include lactose, sucrose,starch, carboxymethylcellulose, calcium carboxymethylcellulose,croscarmellose sodium, sodium carboxymethyl starch, light anhydroussilicic acid and low-substituted hydroxypropylcellulose.

Preferable examples of the solvent include water for injection,physiological brine, Ringer's solution, alcohol, propylene glycol,polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.

Preferable examples of the solubilizing agent include polyethyleneglycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate,ethanol, trisaminomethane, cholesterol, triethanolamine, sodiumcarbonate, sodium citrate, sodium salicylate and sodium acetate.

Preferable examples of the suspending agent include surfactants such asstearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate,lecithin, benzalkonium chloride, benzethonium chloride, glycerolmonostearate and the like; hydrophilic polymers such as poly(vinylalcohol), polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like, polysorbates; and polyoxyethylenehydrogenated castor oil.

Preferable examples of the isotonicity agent include sodium chloride,glycerol, D-mannitol, D-sorbitol and glucose.

Preferable examples of the buffer include buffers of phosphate, acetate,carbonate, citrate etc.

Preferable examples of the soothing agent include benzyl alcohol.

Preferable examples of the preservative include p-oxybenzoate esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid andsorbic acid.

Preferable examples of the antioxidant include sulfite salts andascorbate salts.

Preferable examples of the colorant include aqueous food tar colors(e.g., food colors such as Food Color Red Nos. 2 and 3, Food ColorYellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like foodcolors), water insoluble lake dyes (e.g., aluminum salt of theabove-mentioned aqueous food tar color), natural dyes (e.g., β-carotene,chlorophyll, red iron oxide) and the like.

Preferable examples of the sweetening agent include saccharin sodium,dipotassium glycyrrhizinate, aspartame and stevia.

Examples of the dosage form of the medicament of the present inventioninclude oral preparations such as tablet (including sugar-coated tablet,film-coated tablet, sublingual tablet, orally disintegrating tablet,buccal tablet), capsule (including soft capsule, microcapsule), pill,granule, powder, troche, syrup, liquid, emulsion, suspension, aerosol,films (e.g., orally disintegrable films, oral mucosa-adhesive film) andthe like; and parenteral agents such as injection (e.g., subcutaneousinjection, intravenous injection, intramuscular injection,intraperitoneal injection, drip infusion), external preparation (e.g.,transdermal absorption type preparation, ointment, lotion, adhesivepreparation), suppository (e.g., rectal suppository, vaginalsuppository), pellet, nasal preparation, pulmonary preparation(inhalant), eye drop and the like. Compound (I) and the medicament ofthe present invention can be respectively safely administered orally orparenterally (e.g., intrarectal, intravenous, intraarterial,intramuscular, subcutaneous, intraorgan, intranasal, intradermal,instillation, intracerebral, intravaginal, intraperitoneal,intratumoral, proximal tumor administrations, and administration to thelesion).

These preparations may be a release control preparation (e.g.,sustained-release microcapsule) such as an immediate-releasepreparation, a sustained-release preparation and the like.

While the content of compound (I) in the medicament of the presentinvention varies depending on the dosage form, dose of compound (I) andthe like, it is, for example, about 0.1 to 100 wt %, preferably about0.1 to 50 wt %, more preferably about 0.5 to 20 wt %.

When an oral preparation is produced, coating may be applied wherenecessary for the purpose of taste masking, enteric solubility orsustainability.

Examples of the coating base used for coating include sugar coatingbase, water-soluble film coating base, enteric film coating base, andsustained-release film coating base.

As the sugar-coating base, sucrose is used, and one or is more kindsselected from talc, and the precipitated calcium carbonate, gelatin, gumarabic, pullulan, carnauba wax and the like may be further used incombination.

Examples of the water-soluble film coating base include cellulosepolymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, methylhydroxyethylcellulose and the like;synthetic polymers such as polyvinyl acetal diethylaminoacetate,aminoalkylmethacrylate copolymer E [Eudragit E (trade name)],polyvinylpyrrolidone and the like; and polysaccharides such as pullulanand the like.

Examples of the enteric film coating base include cellulose polymerssuch as hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate,carboxymethylethylcellulose, cellulose acetate phthalate and the like;acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L(trade name)], methacrylic acid copolymer LD [Eudragit L-30D-55 (tradename)], methacrylic acid copolymer S [Eudragit S (trade name)] and thelike; and naturally-occurring substances such as shellac and the like.

Examples of the sustained-release film coating base include cellulosepolymers such as ethylcellulose and the like; and acrylic acid polymerssuch as aminoalkylmethacrylate copolymer RS [Eudragit RS (trade name)],ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE(trade name)] and the like.

Two or more kinds of the above-mentioned coating bases may be used in amixture at an appropriate ratio. In addition, for example, lightshielding agents such as titanium oxide, red ferric oxide and the likemay also be used during coating.

Compound (I) can be used as a prophylactic or therapeutic agent, ordiagnostic agent for the below-mentioned various diseases in mammals(e.g., mice, rats, hamster, rabbits, cats, dogs, cows, sheep, monkeys,humans etc.). Compound (I) can be 15 expected to be useful as an agentfor the prophylaxis or treatment of diseases, for example,

-   (1) psychiatric diseases [e.g., depression, major depression,    bipolar depression, dysthymic disorder, emotional disorder (seasonal    affective disorder and the like), recurrent depression, postpartum    depression, stress disorder, depression symptom, mania, anxiety,    generalized anxiety disorder, anxiety syndrome, panic disorder,    phobia, social phobia, social anxiety disorder, obsessive disorder,    post-traumatic stress syndrome, post-traumatic stress disorder,    Tourette syndrome, autism spectrum disorder, adjustment disorder,    bipolar disorder, neurosis, drug dependence, schizophrenia (e.g.,    positive symptom, negative symptom, cognitive impairment), neurosis,    chronic fatigue syndrome, anxiety neurosis, compulsive neurosis,    panic disorder, epilepsy, anxiety, anxious mental state, emotional    abnormality, cyclothymia, nervous erethism, faint, addiction, low    sex drive, attention deficit hyperactivity disorder (ADHD),    psychotic major depression, refractory major depression,    treatment-resistant depression, cognitive impairment in major    depression],-   (2) genetic diseases associated with psychiatric disorders and    cognitive impairment [e.g., Rett syndrome, fragile X syndrome,    Angelman's syndrome, tuberous sclerosis, RAS/MAPK syndromes    (RASopathy) (e.g., neurofibromatosis type 1, Noonan syndrome, Noonan    syndrome with multiple lentigines, Cardio-facio-cutaneous (CFC)    syndrome, Costello syndrome, Legius syndrome, Leopard syndrome,    capillary malformation-arteriovenous malformation (CM-AVM) syndrome,    Parkes Weber syndrome, etc.), 22q11.2 deletion syndrome]-   (3) neurodegenerative diseases [e.g., Alzheimer's disease,    Alzheimer-type senile dementia, Parkinson's disease, Huntington's    disease, dementia associated with Huntington's disease,    multi-infarct dementia, frontotemporal dementia, Parkinson-type    dementia, frontotemporal dementia Parkinson's Type, progressive    supranuclear palsy, Pick's syndrome, Niemann-Pick syndrome,    corticobasal degeneration, Down's disease, vascular dementia (VaD)    (e.g., multi-infarct dementia, strategic single infarct dementia,    Small vessel disease with dementia, hypoperfusion vascular dementia,    hemorrhagic dementia, chronic subdural hematoma etc.),    postencephalitic parkinsonism, Lewy body dementia, HIV dementia,    amyotrophic lateral sclerosis (ALS), motor neurogenesis disease    (MND), Creutzfeldt-Jakob disease or prion disease, cerebral palsy,    progressive supranuclear palsy, multiple sclerosis,    neurodegeneration accompanying stroke, neurodegeneration    accompanying cerebral infarction],-   (4) age-related cognition memory disorders [e.g., age-related memory    disorders, senile dementia]-   (5) sleep disorders [e.g., intrinsic sleep disorders (e.g.,    psychophysiological insomnia and the like), extrinsic sleep    disorder, circadian rhythm disorders (e.g., time zone change    syndrome (jet lag), shift work sleep disorder, irregular sleep-wake    pattern, delayed sleep phase syndrome, advanced sleep phase    syndrome, non-24-hour sleep-wake and the like), parasomnia, sleep    disorders associated with internal medical or psychiatric disorder    (e.g., chronic obstructive pulmonary diseases, Alzheimer's disease,    Parkinson's disease, cerebrovascular dementia, schizophrenia,    depression, anxiety neurosis), stress insomnia, insomnia, insomniac    neurosis, sleep apnea syndrome],-   (6) respiratory depression caused by anesthetics, traumatic disease,    or neurodegenerative disease and the like,-   (7) traumatic brain injury, stroke, cerebral infarction, cerebral    apoplexy, hearing loss, neurotic anorexia, eating disorder, anorexia    nervosa, hyperorexia, other eating disorder, to alcohol dependence,    alcohol abuse, alcoholic amnesia, alcohol paranoia, alcohol    preference, alcohol withdrawal, alcoholic insanity, alcohol    poisoning, alcoholic jealousy, alcoholic mania, alcohol-dependent    psychiatric disorder, alcoholic insanity, pharmacophilia,    pharmacophobia, pharmacomania, drug is withdrawal, migraine, stress    headache, catatonic headache, diabetic neuropathy, obesity,    diabetes, muscular spasm, Meniere's disease, autonomic ataxia,    alopecia, glaucoma, hypertension, cardiac disease, tachycardia,    cardiac failure, hyperventilation, bronchial asthma, apnea, sudden    infant death syndrome, inflammatory disease, allergic disease,    impotence, climacteric disorder, infertility, cancer,    immunodeficiency syndrome caused by HIV infection, autoimmune    encephalitis (e.g., autoimmune limbic encephalitis),    immunodeficiency syndrome caused by stress, cerebrospinal    meningitis, acromegaly, incontinence, metabolic syndrome,    osteoporosis, peptic ulcer, irritable bowel syndrome, inflammatory    bowel disease, ulcerative colitis, Crohn's disease, stress    gastrointestinal disorder, stress vomiting, stress ulcer, diarrhea,    constipation, postoperative ileus, stress gastrointestinal disorder,    and the like.

In particular, compound (I) can be expected to be useful as an agent forthe prophylaxis or treatment of depression, Alzheimer's disease,schizophrenia, attention deficit hyperactivity disorder (ADHD) and thelike.

Since compound (I) has an excellent AMPA receptor potentiator effect, itis expected to provide an excellent prophylactic or therapeutic effectfor the above-mentioned diseases.

Compound (I) shows excellent solubility in water, the second solution ofJapanese Pharmacopeia Elution Test, or the second solution of JapanesePharmacopoeia Disintegration Test, shows excellent in vivo kinetics(e.g., plasma drug half-life, intracerebral migration, metabolicstability, CYP inhibition), shows low toxicity (e.g., more excellent asa medicament in terms of acute toxicity, chronic toxicity, genetictoxicity, reproductive toxicity, cardiotoxicity, drug interaction,carcinogenicity, phototoxicity, and the like), and also has excellentproperties as a pharmaceutical product such as a few side effects.Therefore, compound (I) can be safely administered orally orparenterally to a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog,bovine, sheep, monkey, human and the like).

The dose of compound (I) varies depending on the subject ofadministration, administration route and symptoms and is notparticularly limited. For example, for oral administration to adultpatients (body weight adult 40 to 80 kg, for example, 60 kg) with theabove-mentioned disease, the dose may be, for example, 0.001 to 1000mg/kg body weight/day, preferably 0.01 to 100 mg/kg body weight/day,more preferably 0.1 to 10 mg/kg body weight/day, as compound (I). Thisamount can be administered in one to three portions per day.

It is also possible to apply compound (I) to each of the above-mentioneddiseases in combination with a drug, or as a combination therapy incombination with therapy method, generally used for the disease.

Examples of other active ingredients (hereinafter, to be referred to asconcomitant drug) to be used in combination with compound (I) includethe following drugs. benzodiazepine (chlordiazepoxide, diazepam,potassium clorazepate, lorazepam, clonazepam, alprazolam etc.), L-typecalcium channel inhibitor (pregabalin etc.), tricyclic or tetracyclicantidepressant (imipramine hydrochloride, amitriptyline hydrochloride,desipramine hydrochloride, clomipramine hydrochloride etc.), selectiveserotonin reuptake inhibitor (fluvoxamine maleate, fluoxetinehydrochloride, 4citalopram hydrobromide, sertraline hydrochloride,paroxetine hydrochloride, escitalopram oxalate etc.),serotonin-noradrenaline reuptake inhibitor (venlafaxine hydrochloride,duloxetine hydrochloride, desvenlafaxine hydrochloride etc.),noradrenaline reuptake inhibitor (reboxetine mesylate etc.),noradrenaline-dopamine reuptake inhibitor (bupropion hydrochlorideetc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride,bupropion hydrochloride, setiptiline maleate, 5-HT_(1A) agonist(buspirone hydrochloride, tandospirone citrate, osemozotan hydroclorideetc.), 5-HT3 antagonist (Cyamemazine etc.), heart non-selective pinhibitor (propranolol hydrochloride, oxprenolol hydrochloride, pindololetc.), histamine Hi antagonist (hydroxyzine hydrochloride etc.),therapeutic drug for schizophrenia (chlorpromazine, haloperidol,sulpiride, clozapine, trifluoperazine hydrochloride, fluphenazinehydrochloride, olanzapine, quetiapine fumarate, risperidone,aripiprazole etc.), CRF antagonist, other antianxiety drug (meprobamateetc.), tachykinin antagonist (aprepitant, saredutant etc.), medicamentthat acts on metabotropic glutamate receptor, medicament that acts onGABA receptor, medicament that acts on acetylcholine receptor, CCKantagonist, β3 adrenaline antagonist (amibegron hydrochloride etc.),GAT-1 inhibitor (tiagabine hydrochloride etc.), N-type calcium channelinhibitor, carbonic anhydrase II inhibitor, NMDA glycine moiety agonist,NMDA antagonist (ketamine, S-ketamine, R-ketamine, ketamine metabolite(e.g., (2S,6S;2R,6R)-hydroxynnorketamine, (2R,6R)-hydroxynnorketamineetc.), memantine etc.), peripheral benzodiazepine receptor agonist,vasopressin antagonist, vasopressin V1b antagonist, vasopressin V1aantagonist, phosphodiesterase inhibitor, opioid antagonist, opioidagonist, uridine, nicotinic acid receptor agonist, thyroid hormone (T3,T4), TSH, TRH, MAO inhibitor (phenelzine sulfate, tranylcyprominesulfate, moclobemide etc.), 5-HT_(2A) antagonist, 5-HT_(2A) inverseagonist, COMT inhibitor (entacapone etc.), therapeutic drug for bipolardisorder (lithium (e.g., lithium carbonate etc.), sodium valproate,lamotrigine, riluzole, felbamate etc.), cannabinoid CB1 antagonist(rimonabant etc.), FAAH inhibitor, sodium channel inhibitor, anti-ADHDdrug (methylphenidate hydrochloride, methamphetamine hydrochlorideetc.), therapeutic drug for alcoholism, therapeutic drug for autism,therapeutic drug for chronic fatigue syndrome, therapeutic drug forspasm, therapeutic drug for fibromyalgia syndrome, therapeutic drug forheadache, therapeutic drug for insomnia (etizolam, zopiclone, triazolam,zolpidem, ramelteon, indiplon etc.), therapeutic drug for quittingsmoking, therapeutic drug for myasthenia gravis, therapeutic drug forcerebral infarction, therapeutic drug for mania, therapeutic drug forhypersomnia, therapeutic drug for pain, therapeutic drug for dysthymia,therapeutic drug for autonomic ataxia, therapeutic drug for male andfemale sexual dysfunction, therapeutic drug for migraine, therapeuticdrug for pathological gambler, therapeutic drug for restless legssyndrome, therapeutic drug for substance addiction, therapeutic drug foralcohol-related syndrome, therapeutic drug for irritable bowel syndrome,therapeutic drug for Alzheimer's disease (donepezil, galanthamine,memantine etc.), therapeutic drug for Parkinson's disease, therapeuticdrug for ALS (riluzole etc., neurotrophic factor etc.), therapeutic drugfor lipid abnormality such as cholesterol-lowering drug (statin series(pravastatin sodium, atrovastatin, simvastatin, rosuvastatin etc.),fibrate (clofibrate etc.), squalene synthetase inhibitor), therapeuticdrug for abnormal behavior or suppressant of dromomania due to dementia(sedatives, antianxiety drug etc.), apoptosis inhibitor, antiobesitydrug, therapeutic drug for diabetes, therapeutic drug for hypertension,therapeutic drug for hypotension, therapeutic drug for rheumatism(DMARD), anti-cancer agent, therapeutic drug for parathyroid (PTH),calcium receptor antagonist, sex hormone or a derivative thereof(progesterone, estradiol, estradiol benzoate etc.), neuronaldifferentiation promoter, nerve regeneration promoter, non-steroidalanti-inflammatory drug (meloxicam, tenoxicam, indomethacin, ibuprofen,celecoxib, rofecoxib, aspirin, indomethacin etc.), steroid(dexamethasone, cortisone acetate etc.), anti-cytokine drug (TNFinhibitor, MAP kinase inhibitor etc.), antibody medicament, nucleic acidor nucleic acid derivative, aptamer drug and the like.

By combining compound (I) and a concomitant drug, a superior effect suchas

-   (1) the dose can be reduced as compared to single administration of    compound (I) or a concomitant drug,-   (2) the drug to be combined with compound (I) can be selected    according to the condition of patients (mild case, severe case and    the like),-   (3) the period of treatment can be set longer by selecting a    concomitant drug having different action and mechanism from compound    (I),-   (4) a sustained treatment effect can be designed by selecting a    concomitant drug having different action and mechanism from compound    (I),-   (5) a synergistic effect can be afforded by a combined use of    compound (I) and a concomitant drug, and the like, can be achieved.

Hereinafter the compound of the present invention and a concomitant drugused in combination are referred to as the “combination agent of thepresent invention”.

When using the combination agent of the present invention, theadministration time of compound (I) and the concomitant drug is notrestricted, and compound (I) or a pharmaceutical composition thereof andthe concomitant drug or a pharmaceutical composition thereof can beadministered to an administration subject simultaneously, or may beadministered at different times. The dosage of the concomitant drug maybe determined according to the dose clinically used, and can beappropriately selected depending on an administration subject,administration route, disease, combination and the like.

The administration mode of the combination agent of the presentinvention is not particularly restricted, and it is sufficient thatcompound (I) and the concomitant drug are combined in administration.Examples of such administration mode include the following methods:

-   (1) administration of a single preparation obtained by    simultaneously processing compound (I) and the concomitant drug, (2)    simultaneous administration of two kinds of preparations of    compound (I) and the concomitant drug, which have been separately    produced, by the same administration route, (3) administration of    two kinds of preparations of compound (I) and the concomitant drug,    which have been separately produced, by the same administration    route in a staggered manner, (4) simultaneous administration of two    kinds of preparations of compound (I) and the concomitant drug,    which have been separately produced, by different administration    routes, (5) administration of two kinds of preparations of    compound (I) and the concomitant drug, which have been separately    produced, by different administration routes in a staggered manner    (for example, administration in the order of the compound of the    present invention and the concomitant drug, or in the reverse order)    and the like.

The combination agent of the present invention can be used as apharmaceutical composition prepared by mixing. compound (I) or(and) theabove-mentioned concomitant drug with a pharmacologically acceptablecarrier, like the medicament of the present invention.

The dosage of the concomitant drug may be appropriately selectedaccording to the dose clinically used. The mixing ratio of compound (I)to the concomitant drug can be appropriately selected depending onadministration subject, route of administration, target disease,symptom, combination and the like.

For example, the content of compound (I) in the combination agent of thepresent invention differs depending on the form of a preparation, andusually from about 0.01 to about 100 wt %, preferably from about 0.1 toabout 50 wt %, further preferably from about 0.5 to about 20 wt %, basedon the preparation.

The content of the concomitant drug in the combination agent of thepresent invention differs depending on the form of a preparation, andusually from about 0.01 to about 100 wt %, preferably from about 0.1 toabout 50 wt %, further preferably from about 0.5 to about 20 wt %, basedon the preparation.

When compound (I) and a concomitant drug are separately formulated intopreparations, the contents thereof are similar to the above.

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples, Experimental Examples and Formulation Examples.However, the examples do not limit the present invention and theexamples can be modified within the 35 scope of the present invention.

The “room temperature” in the following Examples is generally about 10°C. to about 35° C. The ratio for mixed solvent is, unless otherwisespecified, a volume mixing ratio and % means wt % unless otherwisespecified.

The elution by column chromatography in the Examples was performed underthe observation by TLC (Thin Layer Chromatography) unless otherwisespecified. In the observation by TLC, 60 F254 manufactured by Merck wasused as a TLC plate, io the solvent used as an elution solvent in columnchromatography was used as an eluent, and UV detector was used for thedetection. In silica gel column chromatography, the indication of NHmeans use of aminopropylsilane-bonded silica gel and the indication ofDiol means use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silicagel. In preparative HPLC (high performance liquid chromatography), theindication of C18 means use of octadecyl-bonded silica gel. The ratiofor elution solvent is, unless otherwise specified, a volume mixingratio.

For the analysis of ¹1-1 NMR, ACD/SpecManager (trade name) software andthe like were used. Peaks of a hydroxyl group, an amino group, a carboxygroup and the like, having very mild proton peak, are not sometimesdescribed.

MS was measured by LC/MS. As the ionization method, ESI method, or APCImethod was used. The data indicates actual measured value (found). Whilemolecular ion peak is generally observed, a fragment ion is sometimesobserved. In the case of a salt, a molecular ion peak or fragment ionpeak of free form is generally observed.

The unit of sample concentration (c) for optical rotation ([α]_(D)) isg/100 mL.

Elemental analysis value (Anal.) is described as calculated value(Calcd) and actual measured value (Found).

In the following Examples, the following abbreviations are used.

-   mp: melting point-   MS: mass spectrum-   M: mol concentration-   N: normality-   CDCl₃: deuterochloroform-   DMSO-d₆: deuterodimethyl sulfoxide-   ¹H NMR: proton nuclear magnetic resonance-   LC/MS: liquid chromatograph mass spectrometer-   ESI: electrospray ionization-   APCI: atomospheric pressure chemical ionization-   IPE: 2-isopropoxypropane-   AcOH: acetic acid-   HOBt: 1H-benzotriazol-1-ol-   WSC: N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide-   HATU: O-(7-azabenzotriazol-1-yl)-N,N,W,N′-tetramethyluronium-   hexafluorophosphate-   DMSO: (methylsulfinyl)methane-   BS: 1-bromopyrrolidine-2,5-dione-   DIPEA: N-ethyl-N-isopropylpropan-2-amine-   DMF: N,N-dimethylformamide

Example 143-bromo-9-(4-(morpholin-4-ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-oneA) 9-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

A mixture of 3-bromopyridin-2-amine (25 g), ethyl4,4,4-trifluoro-3-oxobutanoate (42.3 mL) and bismuth trichloride (2.28g) was stirred under nitrogen atmosphere, at 150° C. for 8 hr, and thenovernight at 120° C. To the mixture was added 1 M hydrochloric acid atroom temperature, and the mixture was extracted with ethyl acetate. Theorganic layer was separated, washed with 1 M hydrochloric acid andwater, dried over sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give the title compound (16.3 g).

¹H NMR (300 MHz, CDCl₃) δ 6.83 (1H, s), 7.13 (1H, t, J=7.2 Hz), 8.21(1H, d, J=6.8 Hz), 9.07 (1H, d, J=6.8 Hz).

B) ethyl4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoate

A mixture of 9-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one(3.24 g), (4-(ethoxycarbonyl)phenyl)boronic acid (4.29 g),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(0.743 g), 2 M aqueous sodium carbonate solution (11.1 mL) and toluene(100 mL) was stirred at 100° C. for 16 hr. To the mixture was addedwater at room temperature, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (3.59g).

-   MS: [M+H]⁺ 363.2.

C) 4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoicacid

A mixture of ethyl4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoate(3.42 g), conc. hydrochloric acid (17.3 mL) and acetic acid (32.0 mL)was stirred at 80° C. for 5 hr. To the mixture was added water at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was separated, washed with water and saturated brine,dried over sodium sulfate, and concentrated under reduced pressure togive the title compound (2.34 g).

-   MS: [M+H]⁺ 335.2.

D)9-(4-(morpholin-4-ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

A mixture of4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoic acid(383 mg), morpholine (120 mg), WSC hydrochloride (264 mg), anhydrousHOBt (186 mg), triethylamine (0.400 mL) and DMF (6.00 mL) was stirredunder dry atmosphere with calcium chloride tube, at room temperature for18 hr. To the mixture was added water at room temperature, and themixture was extracted with ethyl acetate. The organic layer wasseparated, washed with water and saturated brine, dried over sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/ethyl acetate) togive the title compound (362 mg).

-   MS: [M+H]⁺ 404.1.-   E)    3-bromo-9-(4-(morpholin-4-ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

A mixture of9-(4-(morpholin-4-ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one(2.42 g), NBS (1.18 g) and acetonitrile (50 mL) was stirred under dryingwith calcium chloride tube at 60° C. for 1 hr. To the mixture was addedwater at room temperature, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate/methanol), and the objectivefractions were combined, and concentrated. The obtained solid wastriturated with hexane/ethyl acetate. The solid was collected byfiltration, washed with hexane/ethyl acetate, and the obtained solid wasrecrystallized from hexane/ethyl acetate to give the title compound(2.07 g).

-   ¹H NMR (300 MHz, DMSO-d₆) δ 3.34-3.83 (8H, m), 7.48-7.59 (2H, 35 m),    7.67 (1H, t, J=7.2 Hz), 7.76-7.87 (2H, m), 8.25 (1H, dd, J=7.2, 1.5    Hz), 9.10 (1H, dd, J=7.2, 1.5 Hz).

Example 483-bromo-9-(4-(((2S)-2-methylmorpholin-4-yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-oneA) 9-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

A mixture of 3-bromopyridin-2-amine (25 g), ethyl4,4,4-trifluoro-3-oxobutanoate (42.3 mL) and bismuth trichloride (2.28g) was stirred under nitrogen atmosphere, at 150° C. for 8 hr, and thenovernight at 120° C. To the mixture was added 1 M hydrochloric acid atroom temperature, and the mixture was extracted with ethyl acetate. Theorganic layer was separated, washed with 1 M hydrochloric acid andwater, dried over sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give the title compound (16.3 g).

¹H NMR (300 MHz, CDCl₃) δ 6.83 (1H, s), 7.13 (1H, t, J=7.2 Hz), 8.21(1H, d, J=6.8 Hz), 9.07 (1H, d, J=6.8 Hz).

B) ethyl4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoate

A mixture of 9-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one(3.24 g), (4-(ethoxycarbonyl)phenyl)boronic acid (4.29 g),bis(di-tert-butyl(4-5dimethylaminophenyl)phosphine)dichloropalladium(II)(0.743 g), 2 M aqueous sodium carbonate solution (11.1 mL) and toluene(100 mL) was stirred at 100° C. for 16 hr. To the mixture was addedwater at room temperature, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (3.59g).

MS: [M+H]⁺ 363.2.

C) 4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9- yl)benzoicacid

A mixture of ethyl4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoate(3.42 g), conc.

hydrochloric acid (17.3 mL) and acetic acid (32.0 mL) was stirred at 80°C. for 5 hr. To the mixture was added water at room temperature, and themixture was extracted with ethyl acetate. The organic layer wasseparated, washed with water and saturated brine, dried over sodiumsulfate, and concentrated under reduced pressure to give the titlecompound (2.34 g).

MS: [M+H]⁺ 335.2.

D)9-(4-(((2S)-2-methylmorpholin-4-yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

To a mixture of4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoic acid(1.22 g) and (S)-2-methylmorpholine hydrochloride (0.501 g) in DMF (20mL) were added HATU (2.08 g) and DIPEA (0.956 mL). The mixture wasstirred at room temperature for 3 hr, poured into water, and extractedwith ethyl acetate. The organic layer was washed with water, dried oversodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel 25 column chromatography (hexane/ethyl acetate)to give the title compound (1.53 g).

MS: [M+H]⁺ 418.2.

E)3-bromo-9-(4-(((2S)-2-methylmorpholin-4-yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

A mixture of9-(4-M2S)-2-methylmorpholin-4-yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one(1.53 g), NBS (0.719 g) and acetonitrile (40 mL) was stirred under dryatmosphere with calcium chloride tube, at room temperature for 2 hr. Tothe mixture was added water at room temperature, and the mixture wasextracted with ethyl acetate. The organic layer was separated, washedwith water and saturated brine, dried over sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate/methanol), andrecrystallized (hexane/ethyl acetate) to give the title compound (1.36g).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80-1.36 (3H, m), 2.76-3.35 (2H, m),3.36-4.04 (4H, m), 4.15-4.67 (1H, m), 7.49-7.59 (2H, m), 7.67 (1H, t,J=7.2 Hz), 7.76-7.86 (2H, m), 8.25 (1H, dd, J=7.2, 1.5 Hz), 9.10 (1H,dd, J=7.2, 1.5 Hz).

Example 934-(3-methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3S)-tetrahydro-2H-pyran-3-yl)benzamideA) 9-bromo-3-methyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

A mixture of 3-bromopyridin-2-amine (5 g), ethyl4,4,4-trifluoro-2-methyl-3-oxobutanoate (11.5 g) and bismuth trichloride(0.456 g) was stirred under nitrogen atmosphere at 120° C. for 2 hr, andthen at 150° C. for 18 hr. To the mixture were added ethyl4,4,4-trifluoro-2-methyl-3-oxobutanoate (5 mL) and bismuth trichloride(0.3 g), and the mixture was stirred at 150° C. for 42 hr. To themixture was added 1M hydrochloric acid at room temperature, and themixture was extracted with ethyl acetate. The organic layer wasseparated, washed with 1M hydrochloric acid and water, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate), the eluate was concentrated, and the residue was washed withhexane to give the title compound (1.73 g).

MS: [M+H]⁺ 307.0.

B) ethyl4-(3-methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoate

A mixture of9-bromo-3-methyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one(1.73 g), (4-(ethoxycarbonyl)phenyl)boronic acid (2.19 g),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(0.379 g), 2 M aqueous sodium carbonate solution (5.63 mL) and toluene(40.0 mL) was stirred at 100° C. for 16 hr. To the mixture was addedwater at room temperature, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate), the eluate was concentrated, andthe residue was washed with diisopropyl ether to give the title compound(1.86 g).

MS: [M+H]⁺ 377.2.

C)4-(3-methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoicacid

A mixture of ethyl4-(3-methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoate(1.83 g), conc. hydrochloric acid (8.92 mL) and AcOH (16.2 mL) wasstirred at 80° C. for 5 hr. The precipitated solid was collected byfiltration, and washed with diethyl ether and hexane to give the titlecompound (1.40 g).

¹H NMR (300 MHz, DMSO-d₆) δ 2.24-2.34 (3H, m), 7.54 (1H, t, J=7.2 Hz),7.80-7.88 (2H, m), 7.96-8.07 (2H, m), 8.11 (1H, dd, J=7.2, 1.5 Hz), 9.03(1H, dd, J=7.2, 1.5 Hz).

D)4-(3-methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3S)-tetrahydro-2H-pyran-3-yl)benzamide

A mixture of4-(3-methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoicacid (60 mg), HATU (98 mg), DIPEA (0.060 mL),(S)-tetrahydro-2H-pyran-3-amine hydrochloride (28.4 mg) and DMF (2 mL)was stirred overnight at room temperature. To the mixture was addedsilica gel, the mixture was concentrated, and the residue was purifiedby silica gel column chromatography (NH, hexane/ethyl acetate) to givethe title compound (63.6 mg).

MS: [M+H]⁺ 307.0.

¹H NMR (300 MHz, DMSO-d₆) δ 1.42-1.78 (3H, m), 1.94 (1H, br. s.), 2.30(3H, d, J=1.9 Hz), 3.08-3.25 (1H, m), 3.23-3.39 (1H, m), 3.71-3.87 (2H,m), 3.88-4.05 (1H, m), 7.54 (1H, t, J=7.2 Hz), 7.74-7.88 (2H, m),7.90-8.02 (2H, m), 8.10 (1H, dd, J=7.0, 1.3 Hz), 8.32 (1H, d, J=7.9 Hz),9.03 (1H, dd, J=7.2, 1.1 Hz)

Example 121 optical isomer of1-(4-(3-methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoyl)pyrrolidine-3-carbonitrile(longer retention time) A)9-bromo-3-methyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

A mixture of 3-bromopyridin-2-amine (5 g), ethyl4,4,4-trifluoro-2-methyl-3-oxobutanoate (11.5 g) and bismuth trichloride(0.456 g) was stirred under nitrogen atmosphere at 120° C. for 2 hr, andthen at 150° C. for 18 hr. Ethyl 4,4,4-trifluoro-2-methyl-3-oxobutanoate(5 mL) and bismuth trichloride (0.3 g) were added thereto, and themixture was stirred at 150° C. for 42 hr. To the mixture was added 1Mhydrochloric acid at room temperature, and the mixture was extractedwith ethyl acetate. The organic layer was separated, washed with 1Mhydrochloric acid and water, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane/ethyl acetate), the eluate wasconcentrated, and the residue was washed with hexane to give the titlecompound (1.73 g).

MS: [M+H]⁺ 307.0.

B) ethyl4-(3-methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoate

A mixture of9-bromo-3-methyl-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one(1.73 g), (4-(ethoxycarbonyl)phenyl)boronic acid (2.19 g),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(0.379 g), 2 M aqueous sodium carbonate solution (5.63 mL) and toluene(40.0 mL) was refluxed at 100° C. for 16 hr. To the mixture was addedwater at room temperature, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (1.86g).

MS: [M+H]⁺ 377.2.

C)4-(3-methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoicacid

A mixture of ethyl4-(3-methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoate(1.83 g), conc. hydrochloric acid (8.92 mL) and AcOH (16.2 mL) wasstirred at 80° C. for 5 hr. The precipitated solid was collected byfiltration, and washed with diethyl ether and hexane to give the titlecompound (1.40 g).

¹H NMR (300 MHz, DMSO-dd 5 2.24-2.34 (3H, m), 7.54 (1H, t, J=7.2 Hz),7.80-7.88 (2H, m), 7.96-8.07 (2H, m), 8.11 (1H, dd, J=7.2, 1.5 Hz), 9.03(1H, dd, J=7.2, 1.5 Hz).

D) optical isomer of1-(4-(3-methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoyl)pyrrolidine-3-carbonitrile(longer retention time)

A mixture of4-(3-methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoicacid (100 mg), pyrrolidine-3-carbonitrile hydrochloride (41.9 mg), HATU(164 mg), DIPEA (37.7 mg) and DMF (2 mL) was stirred overnight at roomtemperature. To the mixture was added silica gel, the mixture wasconcentrated, and the residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give a racemate (93 mg) of thetitle compound. MS: [M+H]⁺ 427.1

¹H NMR (300 MHz, DMSO-d₆) δ 2.10-2.40 (5H, m), 3.38-3.76 (4H, m),3.77-3.94 (1H, m), 7.54 (1H, t, J=7.0 Hz), 7.66 (2H, d, J=8.7 Hz), 7.83(2H, d, J=8.3 Hz), 8.07-8.15 (1H, m), 9.03 (1H, dd, J=7.2, 1.5 Hz)

The racemate (91 mg) was resolved by HPLC (column: CHIRALPAK IA, 50mmIDx500 mmL, Manufactured by Daicel Chemical Industries, mobile phase:methanol/trifluoroethanol), and the fraction having a longer retentiontime was concentrated to 15 give the title compound (31 mg).

MS: [M+H]⁺ 427.2.

Example 1224-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3S)-tetrahydro-2H-pyran-3-yl)benzamideA) 9-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

A mixture of 3-bromopyridin-2-amine (25 g), ethyl4,4,4-trifluoro-3-oxobutanoate (42.3 mL) and bismuth trichloride (2.28g) was stirred under nitrogen atmosphere at 150° C. for 8 hr, and thenovernight at 120° C. To the mixture was added 1 M hydrochloric acid atroom temperature, and the mixture was extracted with ethyl acetate. Theorganic layer was separated, washed with 1 M hydrochloric acid andwater, dried over sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give the title compound (16.3 g).

¹H NMR (300 MHz, CDCl₃) δ 6.83 (1H, s), 7.13 (1H, t, J=7.2 Hz), 8.21(1H, d, J=6.8 Hz), 9.07 (1H, d, J=6.8 Hz).

B) ethyl4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoate

A mixture of 9-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one(3.24 g), (4-(ethoxycarbonyl)phenyl)boronic acid (4.29 g),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(0.743 g), 2 M aqueous sodium carbonate solution (11.1 mL) and toluene(100 mL) was stirred at 100° C. for 16 hr. To the mixture was addedwater at room temperature, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (3.59g).

MS: [M+H]⁺ 363.2.

C) 4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9- yl)benzoicacid

A mixture of ethyl4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoate(3.42 g), conc. hydrochloric acid (17.3 mL) and acetic acid (32.0 mL)was stirred at 80° C. for 5 hr. To the mixture was added water at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was separated, washed with water and saturated brine,dried over sodium sulfate, and concentrated under reduced pressure togive the title compound (2.34 g).

MS: [M+H]⁺ 335.2.

D) 4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3S)-tetrahydro-2H-pyran-3-yl)benzamide

A mixture of4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoic acid(100 mg), HATU (171 mg), DIPEA (0.051 mL),(3S)-tetrahydro-2H-pyran-3-amine hydrochloride (41.2 mg) and DMF (2 mL)was stirred overnight. Silica gel was added thereto, the mixture wasconcentrated, and the residue was purified by silica gel columnchromatography (NH, hexane/ethyl acetate) to give the title compound(119 mg). ¹H NMR (300 MHz, DMSO-d₆) δ 1.46-1.78 (3H, m), 1.94 (1H, br.s.), 3.19 (1H, t, J=10.0 Hz), 3.26-3.35 (1H, m), 3.66-3.87 (2H, m),3.87-4.07 (1H, m), 6.89 (1H, s), 7.60 (1H, t, J=7.2 Hz), 7.79 (2H, d,J=8.3 Hz), 7.95 (2H, d, J=8.7 Hz), 8.20 (1H, dd, J=7.2, 1.5 Hz), 8.33(1H, d, J=7.9 Hz), 9.10 (1H, dd, J=7.2, 1.5 Hz)

Example 1234-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamideA) 9-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

A mixture of 3-bromopyridin-2-amine (25 g), ethyl4,4,4-trifluoro-3-oxobutanoate (42.3 mL) and bismuth trichloride (2.28g) was stirred under nitrogen atmosphere, at 150° C. for 8 hr, and thenovernight at 120° C. To the mixture was added 1 M hydrochloric acid atroom temperature, and the mixture was extracted with ethyl acetate. Theorganic layer was separated, washed with 1 M hydrochloric acid andwater, dried over sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate) to give the title compound (16.3 g).

¹H NMR (300 MHz, CDCl3) 5 6.83 (1H, s), 7.13 (1H, t, J=7.2 Hz), 8.21(1H, d, J=6.8 Hz), 9.07 (1H, d, J=6.8 Hz).

B) ethyl4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoate

A mixture of 9-bromo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one(3.24 g), (4-(ethoxycarbonyl)phenyl)boronic acid (4.29 g),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(0.743 g), 2 M aqueous sodium carbonate solution (11.1 mL) and toluene(100 mL) was stirred at 100° C. for 16 hr. To the mixture was addedwater at room temperature, and the mixture was extracted with ethylacetate. The organic layer was separated, washed with water andsaturated brine, dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/ethyl acetate) to give the title compound (3.59g).

MS: [M+H]⁺ 363.2.

C) 4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9- yl)benzoicacid

A mixture of ethyl4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoate(3.42 g), conc. hydrochloric acid (17.3 mL) and acetic acid (32.0 mL)was is stirred at 80° C. for 5 hr. To the mixture was added water atroom temperature, and the mixture was extracted with ethyl acetate. Theorganic layer was separated, washed with water and saturated brine,dried over sodium sulfate, and concentrated under reduced pressure togive the title compound (2.34 g).

MS: [M+H]⁺ 335.2.

D)4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide

A mixture of4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)benzoic acid(100 mg), HATU (171 mg), DIPEA (0.051 mL), tetrahydro-2H-pyran-4-aminehydrochloride (45.3 mg) and DMF (2 mL) was stirred overnight at roomtemperature. Silica gel was added thereto, and the mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (NH, hexane/ethyl acetate), the eluate wasconcentrated, and the residue was triturated with water/IPE to give thetitle compound (118 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.45-1.72 (2H, m), 1.72-1.87 (2H, m),3.34-3.47 (2H, m), 3.76-3.95 (2H, m), 3.95-4.15 (1H, m), 6.90 (1H, s),7.60 (1H, t, J=7.2 Hz), 7.80 (2H, d, J=8.3 Hz), 7.90-7.99 (2H, m), 8.20(1H, dd, J=7.2, 1.5 Hz), 8.42 (1H, d, J=7.5 Hz), 9.10 (1H, dd, J=7.2,1.5 Hz)

The compounds of Examples are shown in the following

Table 1-1 to Table 1-19. MS in the tables means actual measured value.The compounds of Examples 1-13, 15-47, 49-92, 94-120 and 124-133 in thefollowing tables were produced according to the methods described in theabove-mentioned Examples, or methods analogous thereto.

TABLE 1-1 EXAMPLE IUPAC NAME Structure ADDITIVE MS 1N-methyl-4-(4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(2,2,2- trifluoroethyl)benzamide

430.1 2 N-(2,2-difluoroethyl)-N-methyl-4- (4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9- yl)benzamide

412.1 3 9-(4-((3,3-difluoropiperidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

438.1 4 9-(4-((2,2-difluoromorpholin-4- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

440.1 5 N-(1-(difluoromethyl)cyclopropyl)-4-(4-oxo-2-(trifluoromethyl)-4H- pyrido[1,2-a]pyrimidin-9- yl)benzamide

422.0 6 9-(4-((3-hydroxy-3- (trifluoromethyl)pyrrolidin-1-yl)carbonyl)phenyl)-2 (trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

472.1 7 9-(4-((4-hydroxy-4- methylpiperidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

432.2

TABLE 1-2 EXAMPLE IUPAC NAME Structure ADDITIVE MS 8 9-(4-((4-ethyl-4-hydroxypiperidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

446.2 9 9-(4-((4-hydroxypiperidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

418.1 10 9-(4-((3,3-difluoro-4- hydroxypiperidin-1-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

454.1 11 9-(4-((3- (hydroxymethyl)pyrrolidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

418.1 12 N-(2-cyanoethyl)-N-methyl-4-(4- oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9- yl)benzamide

401.1 13 N-(cyclopropylmethyl)-N-methyl-4-(4-oxo-2-(trifluoromethyl)-4H- pyrido[1,2-a]pyrimidin-9- yl)benzamide

402.1 14 3-bromo-9-(4-(morpholin-4- ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

481.9

TABLE 1-3 EXAMPLE IUPAC NAME Structure ADDITIVE MS 159-(4-((3-hydroxy-3- (trifluoromethyl)pyrrolidin-1-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one optical isomer (retention time: shorter)

472.1 16 9-(4-((3-hydroxy-3- (trifluoromethyl)pyrrolidin-1-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one optical isomer (retention time: longer)

472.0 17 3-chloro-9-(4-(morpholin-4- ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

438.0 18 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-methyl-N- (tetrahydro-2H-pyran-4- yl)benzamide

509.8 19 3-bromo-9-(4-((2,2- difluoromorpholin-4- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

517.9 20 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(3- methoxypropyl)benzamide

483.9 21 3-bromo-9-(4-(piperidin-1- ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

479.9

TABLE 1-4 EXAMPLE IUPAC NAME Structure ADDITIVE MS 229-(3-fluoro-4-(((2S)-2- methylmorpholin-4- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

436.1 23 9-(4-((2- (difluoromethyl)morpholin-4-yl)carbonyl)phenyl)-3-methyl-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

468.1 24 9-(4-((3,3-difluoroazetidin-1- yl)carbonyl)phenyl)-3-methyl-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

424.0 25 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(2- cyanoethyl)-N-ethylbenzamide

493.0 26 N-(2,2-difluoroethyl)-4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-9-yl)benzamide

396.0 27 9-(4-((3-hydroxy-3- methylpiperidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

432.2 28 9-(4-((3-hydroxy-3- methylpyrrolidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

418.1

TABLE 1-5 EXAMPLE IUPAC NAME Structure ADDITIVE MS 29 9-(4-((3-ethyl-3-hydroxypiperidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

446.2 30 9-(4-((3-hydroxy-3- methylazetidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

404.1 31 9-(4-((3-(difluoromethyl)-3- hydroxypyrrolidin-1-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

454.1 32 9-(4-(((3S)-3-hydroxypyrrolidin- 1-yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

404.1 33 9-(4-((4-hydroxy-4- (trifluoromethyl)piperidin-1-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

486.1 34 N-ethyl-4-(4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(2,2,2- trifluoroethyl)benzamide

444.2 35 4-(3-chloro-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(2,2,2- trifluoroethyl)benzamide

447.9

TABLE 1-6 EXAMPLE IUPAC NAME Structure ADDITIVE MS 369-(4-((3-hydroxy-3- (trifluoromethyl)piperidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

486.1 37 3-methyl-9-(4-(morpholin-4- ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

418.0 38 1-(4-(3-chloro-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9- yl)benzoyl)piperidine-3-carbonitrile

461.1 39 4-(3-chloro-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(2- cyanoethyl)-N-methylbenzamide

435.0 40 3-chloro-9-(4-((3,3- difluoropyrrolidin-1-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

458.1 41 4-(3-chloro-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(2,2- difluoroethyl)-N-methylbenzamide

446.0 42 N-(2,2-difluoroethyl)-2-fluoro-4- (4-oxo-2-trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9- yl)benzamide

413.9

TABLE 1-7 EXAMPLE IUPAC NAME Structure ADDITIVE MS 432-fluoro-4-(4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(2,2,2- trifluoroethyl)benzamide

431.9 44 9-(3-fluoro-4-(morpholin-4- ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

422.0 45 9-(3-fluoro-4-(morpholin-4- ylcarbonyl)phenyl)-3-methyl-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

436.0 46 3-bromo-9-(3-fluoro-4- (morpholin-4-ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

499.9 47 3-bromo-9-(4-(1,4-oxazepan-4- ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

496.0 48 3-bromo-9-(4-(((2S)-2- methylmorpholin-4-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

495.9 49 3-bromo-9-(4-(((2R)-2- methylmorpholin-4-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

495.9

TABLE 1-8 EXAMPLE IUPAC NAME Structure ADDITIVE MS 503-bromo-9-(4-(((3S)-3- methoxypyrrolidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

495.8 51 3-bromo-9-(4-(((3R)-3- methoxypyrrolidin-1-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

496.0 52 3-bromo-9-(4-((4- methoxypiperidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

510.0 53 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(oxetan-3- ylmethyl)benzamide

481.8 54 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3R)- tetrahydrofuran-3-yl)benzamide

479.9 55 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3S)- tetrahydrofuran-3-yl)benzamide

481.9 56 3-bromo-9-(4-(1-oxa-7- azaspiro[3.5]non-7-ylcarbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

522.0

TABLE 1-9 EXAMPLE IUPAC NAME Structure ADDITIVE MS 574-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(tetrahydro- 2H-pyran-4-yl)benzamide

495.9 58 3-bromo-9-(4-((3- methoxyazetidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

481.8 59 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(3- ethoxypropyl)benzamide

497.8 60 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-ethyl-N-(2- methoxyethyl)benzamide

498.0 61 9-(4-(azetidin-1- ylcarbonyl)phenyl)-3-bromo-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

451.9 62 3-bromo-9-(4-(pyrrolidin-1- ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

465.9 63 3-bromo-9-(4-((3- (difluoromethoxy)pyrrolidin-1-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

531.9

TABLE 1-10 EXAMPLE IUPAC NAME Structure ADDITIVE MS 643-bromo-9-(4-((3-cyclopropyl-3- hydroxyazetidin-1-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

508.0 65 3-bromo-9-(4-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-1-ylcarbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

514.9 66 3-methyl-9-(4-(((2R)-2- methylmorpholin-4-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

432.1 67 3-methyl-9-(4-(((2S)2- methylmorpholin-4-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

432.1 68 9-(4-((2,2-difluoromorpholin-4- yl)carbonyl)phenyl)-3-methyl-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

454.0 69 3-methyl-9-(4-(1,4-oxazepan-4- ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

432.1 70 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N- (cyclopropylmethyl)-2- fluorobenzamide

484.0

TABLE 1-11 EXAMPLE IUPAC NAME Structure ADDITIVE MS 713-bromo-9-(4-((2,2- difluoromorpholin-4-yl)carbonyl)- 3-f1uorophenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

535.8 72 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-fluoro-N-(2- methoxyethyl)benzamide

488.0 73 3-bromo-9-(3-fluoro-4-(((2S)-2- methylmorpholin-4-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

513.9 74 3-bromo-9-(3-fluoro-4-(((2R)-2- methylmorpholin-4-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

514.0 75 3-bromo-9-(3-fluoro-4-(1,4- oxazepan-4-ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

513.9 76 9-(3-fluoro-4-(1,4-oxazepan-4- ylcarbonyl)phenyl)-3-methyl-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

450.0 77 9-(2-fluoro-4-(1,4-oxazepan-4- ylcarbonyl)phenyl)-3-methyl-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

450.0

TABLE 1-12 EXAMPLE IUPAC NAME Structure ADDITIVE MS 789-(4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-1-ylcarbonyl)-3-fluorophenyl)-2-(trifluoromethyl)- 4H-pyrido[1,2-a]pyrimidin-4-one

455.0 79 3-bromo-9-(4-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-1-ylcarbonyl)-3-fluorophenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

533.0 80 9-(4-(2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-1-ylcarbonyl)-3-fluorophenyl)-3-methyl-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

469.1 81 3-chloro-9-(3-fluoro-4-(1,4- oxazepan-4-ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

470.0 82 2-fluoro-N-methyl-4-(4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(tetrahydro- 2H-pyran-4-yl)benzamide

450.0 83 2-fluoro-N-methyl-4-(3-methyl- 4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N- (tetrahydro-2H-pyran-4- yl)benzamide

464.1 84 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-fluoro-N- methyl-N-(tetrahydro-2H-pyran-4-yl)benzamide

528.0

TABLE 1-13 EXAMPLE IUPAC NAME Structure ADDITIVE MS 852-fluoro-4-(3-methyl-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(tetrahydro- 2H-pyran-4-yl)benzamide

450.0 86 2-fluoro-4-(3-methyl-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3S)- tetrahydrofuran-3-yl)benzamide

436.1 87 9-(3-fluoro-4-((4- methoxypiperidin-1-yl)carbonyl)phenyl)-3-methyl-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

464.1 88 3-bromo-9-(3-fluoro-4-((4- methoxypiperidin-1-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

528.0 89 9-(3-fluoro-4-((4- methoxypiperidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

450.1 90 9-(3-fluoro-4-(((3R)-3- methoxypyrrolidin-1-yl)carbonyl)phenyl)-3-methyl-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

450.0 91 3-bromo-9-(3-fluoro-4-(((3R)-3- methoxypyrrolidin-1-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

514.0

TABLE 1-14 EXAMPLE IUPAC NAME Structure ADDITIVE MS 924-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3S)- tetrahydro-2H-pyran-3- yl)benzamide

496.0 93 4-(3-methyl-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3S)- tetrahydro-2H-pyran-3- yl)benzamide

432.1 94 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-cyclopropyl- 2-fluoro-N-methylbenzamide

483.9 95 4-(3-bromo-4-oxo-2 (trifluoromethyl)-4H-pyrido[1,2a]pyrimidin-9-yl)-N-cyclopropyl- N-ethyl-2-fluorobenzamide

497.9 96 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N- (cyclopropylmethyl)-2-fluoro-N- methylbenzamide

498.0 97 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-fluoro-N- methyl-N-(1- methylcyclopropyl)benzamide

497.9 98 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N- (cyclobutylmethyl)-2-fluoro-N- methylbenzamide

512.0

TABLE 1-15 EXAMPLE IUPAC NAME Structure ADDITIVE MS 994-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(2- cyanoethyl)-N-methylbenzamide

478.9 100 N-(2-cyanoethyl)-N-methyl-4-(3-methyl-4-oxo-2-(trifluoromethyl)- 4H-pyrido[1,2-a]pyrimidin-9-yl)benzamide

415.0 101 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3R)- tetrahydro-2H-pyran-3- yl)benzamide

496.0 102 4-(3-methyl-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3R)- tetrahydro-2H-pyran-3- yl)benzamide

432.1 103 3-bromo-9-(4-((2- (difluoromethyl)morpholin-4-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

531.9 104 3-bromo-9-(4-((3,3- difluoroazetidin-1- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

487.8 105 1-(4-(3-methyl-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9- yl)benzoyl)pyrrolidine-3- carbonitrile

427.1

TABLE 1-16 EXAMPLE IUPAC NAME Structure ADDITIVE MS 106 9-(4-((2-(difluoromethyl)morpholin-4- yl)carbonyl)phenyl)-3-methyl-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one optical isomer(retention time: shorter)

468.1 107 9-(4-((2- (difluoromethyl)morpholin-4-yl)carbonyl)phenyl)-3-methyl-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one optical isomer (retention time: longer)

468.0 108 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(3- hydroxypropyl)-N- methylbenzamide

484.0 109 3-bromo-9-(4-(2-oxa-5- azabicyclo[4.1.0]hept-5-ylcarbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one

493.8 110 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-fluoro-N- ((3S)-tetrahydro-2H-pyran-3- yl)benzamide

514.0 111 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-fluoro-N- ((3R)-tetrahydro-2H-pyran-3- yl)benzamide

514.0 112 1-(4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9- yl)benzoyl)pyrrolidine-3- carbonitrile

491.0

TABLE 1-17 EXAMPLE IUPAC NAME Structure ADDITIVE MS 1133-bromo-9-(4-((2- (difluoromethyl)morpholin-4- yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one optical isomer(retention time: shorter)

531.9 114 3-bromo-9-(4-((2- (difluoromethyl)morpholin-4-yl)carbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one optical isomer (retention time: longer)

531.9 115 2-fluoro-4-(3-methyl-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3S)- tetrahydro-2H-pyran-3- yl)benzamide

450.1 116 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N- (cyclopropylmethyl)-N- methylbenzamide

480.0 117 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-cyclopropyl- N-methylbenzamide

465.9 118 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((1- cyanocyclopropyl)methyl)-N- methylbenzamide

505.0 119 3-bromo-9-(4-((6,6-difluoro-1,4-oxazepan-4-yl)carbonyl)phenyl)- 2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one

532.0

TABLE 1-18 EXAMPLE IUPAC NAME Structure ADDITIVE MS 1201-(4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-9-yl)benzoyl)pyrrolidine-3- carbonitrile optical isomer (retention time:longer)

490.9 121 1-(4-(3-methyl-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9- yl)benzoyl)pyrrolidine-3- carbonitrile optical isomer(retention time: longer)

427.1 122 4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N- ((3S)-tetrahydro-2H-pyran-3-yl)benzamide

418.0 123 4-(4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N- (tetrahydro-2H-pyran-4- yl)benzamide

416.0 124 4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-2-fluoro-N- (tetrahydro-2H-pyran-4- yl)benzamide

512.0 125 4-(3-methyl-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(tetrahydro- 2H-pyran-4-yl)benzamide

432.1 126 (2R)-4-(4-(3-bromo-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9- yl)benzoyl)morpholine-2- carbonitrile

506.9

TABLE 1-19 EXAMPLE IUPAC NAME Structure ADDITIVE MS 1273-bromo-9-(4-(2-oxa-5- azabicyclo[4.1.0]hept-5- ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-one optical isomer(retention time: shorter)

494.0 128 3-bromo-9-(4-(2-oxa-5 azabicyclo[4.1.0]hept-5-ylcarbonyl)phenyl)-2- (trifluoromethyl)-4H-pyrido[1,2- a]pyrimidin-4-oneoptical isomer (retention time: longer)

493.9 129 9-(4-((3,3-difluoroazetidin-1- yl)carbonyl)-3-fluorophenyl)-3-methyl-2-(trifluoromethyl)-4H- pyrido[1,2-a]pyrimidin-4-one

440.1 130 3-bromo-9-(4-((3,3- difluoroazetidin-1-yl)carbonyl)-3-fluorophenyl)-2-(trifluoromethyl)- 4H-pyrido[1,2-a]pyrimidin-4-one

504.0 131 4-(3-chloro-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-(tetrahydro- 2H-pyran-4-yl)benzamide

450.0 132 4-(3-chloro-4-oxo-2- (trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3S)- tetrahydro-2H-pyran-3- yl)benzamide

452.1 133 9-(4-(morpholin-4- ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrazino[1,2- a]pyrimidin-4-one

405.0

In Examples 15, 16, 106, 107, 113, 114, 120, 121, 127 and 128, theoptical isomer was obtained by resolving each racemate by the samemanner as in Step D) of Example 121. The compound obtained from thefraction having a longer retention time is indicated as “longerretention time”, whereas the compound obtained from the fraction havinga shorter retention time is indicated as “shorter retention time”.

In Examples 15 and 16, HPLC (column: CHIRALPAK AS-H, 20 mmID×250 mmL,Manufactured by Daicel Chemical Industries, mobile phase: Carbondioxide/Methanol =840/160(v/v)) was used.

In Examples 106 and 107, HPLC (column: CHIRALPAK AS-H, 20 mmIDx250 mmL,Manufactured by Daicel Chemical Industries, mobile phase: Carbondioxide/Methanol =840/160(v/v)) was used.

In Examples 113 and 114, HPLC (column: CHIRALPAK AS-H, 20 mmIDx250 mmL,Manufactured by Daicel Chemical Industries, mobile phase: Carbondioxide/Methanol =800/200(v/v)) was used.

In Example 120, HPLC (column: CHIRALPAK IA, 50 mmIDx500 mmL,Manufactured by Daicel Chemical Industries, mobile phase: methanol) wasused.

In Example 121, HPLC (column: CHIRALPAK IA, 50 mmIDx500 mmL,Manufactured by Daicel Chemical Industries, mobile phase: methanol) wasused.

In Examples 127 and 128, HPLC (column: CHIRALPAK AS-H, 20 mmIDx250 mmL,Manufactured by Daicel Chemical Industries, mobile phase: Carbondioxide/Methanol =700/300(v/v)) was used.

Experimental Example 1 Measurement Method of AMPA ReceptorFunction-Enhancing Activity of Compound Using Calcium Influx as Index(1) Construction of Expression Gene

Human GluR¹ flip cDNA was amplified by PCR method using forward primerACTGAATTCGCCACCATGCAGCACATTTTTGCCTTCTTCTGC (SEQ ID NO: 1) and reverseprimer CCGCGGCCGCTTACAATCCCGTGGCTCCCAAG (SEQ ID NO: 2) artificiallysynthesized using human brain-derived cDNA (BD Bioscience) as atemplate. The amplified product was digested with restriction enzymesEcoRI, Notl (TAKARA SHUZO CO. LTD.) and incorporated into the same siteof pcDNA3.1 (+) (Invitrogen) to construct pcDNA3.1(+)/human GluR1 flipgene. Human stargazin cDNA was amplified by PCR method using forwardprimer GGTCTCGAGGCCACCATGGGGCTGTTTGATCGAGGTGTTCA (SEQ ID NO: 3) andreverse primer GTTGGATCCTTATACGGGGGTGGTCCGGCGGTTGGCTGTG (SEQ ID NO: 4)artificially synthesized using human hippocampus cDNA as a template. Theamplified product was digested with restriction enzymes Xhol, BamHI(TAKARA SHUZO CO. LTD.) and incorporated into the same site ofpcDNA3.1(−) (Invitrogen) to construct pcDNA3.1 Zeo(−)/human stargazinggene.

(2) Construction of GluR1 Flip/Stargazin Expressing Cell

CHO-K1 cells passaged in a culture medium (Ham's F12 medium (Invitrogen)added with 10% inactivated fetal bovine serum (Morgate) and penicillin,streptomycin (Invitrogen)) were detached using 0.05% trypsin and 0.53 mMEDTA (Invitrogen) diluted with D-PBS(−). The detached cells weresuspended in a culture medium, and recovered by centrifugation at 1,000rpm. The recovered cells were re-suspended in D-PBS(−) and added into0.4 cm electroporation cuvette (BioRad). pcDNA3.1(+)/human GluR1 flipgene (5 μg) and pcDNA3.1 Zeo(−)/human stargazin gene (15 μg) were added,and introduced into CHO-K1 cells under the conditions of 950 μFd, 250 mVand using Gene Pulser II (BioRad). The introduced cells were culturedovernight in a culture medium. The next day, using a selection medium(culture medium added with zeocin (Invitrogen) at 250 μg/mL), the cellswere plated in a 96 well plate at 250 cells/well. The clones showingdrug resistance were selected, and GluR1 flip/stargazin expressionclones were selected by an assay method shown below using calcium influxas an index.

(3) Measurement Method of AMPA Receptor Function-Enhancing Activity ofCompound, Using Calcium Influx as an Index CHO-K1/GluR1flip/stargazin-expressing cells were plated on a 384 well black bottomtransparent plate, and cultured for 2 days in a CO₂ incubator (SANYOELECTRIC Co. Ltd.) at 37° C. The medium of the cell plate was removed. Acalcium indicator (Calcium5 Assay Kit, Molecular Devices) was dilutedwith an assay buffer (HESS (Thermo Fisher Scientific), 0.1% BSA (MerckMillipoer) and 10 mM HEPES (Thermo Fisher Scientific)), and 1.25 mMprobenecid (Dojindo Laboratories) was added thereto. The mixtureprepared above was added at 30 μL/well (100 μL/well in case of 96 wells)to the well, and the well was left standing in 37° C., CO₂ incubator for1 hr. The cell plate was set in CellLux (PerkinElmer), a mixture (15 μL)(50 μL/well in case of 96 wells) of 9 mM glutamic acid (finalconcentration 3 mM) diluted with an assay buffer and a test compound(test compound concentration 30 μM) was added thereto, and variation inthe amount of fluorescence was measured for 3 min. The variation offluorescence level of a well added with final concentration 3 mM ofglutamic acid and 300 pM cyclothiazide (TOCRIS) was defined as 100%, thevariation of fluorescence level of a well added with final concentration3 mM of glutamic acid alone was defined as 0%, and the activity of thecompound was calculated by the following formula.

activity (%)=(X−C)/(T−C)×100

-   T: variation of fluorescence level of well added with final    concentration 3 mM of glutamic acid and 300 μM cyclothiazide-   C: variation of fluorescence level of well added with final    concentration 3 mM of glutamic acid alone-   X: variation of fluorescence level of well added with test compound

The results are shown in Table 2-1 to Table 2-3.

TABLE 2 Example No. hGluR1 flip/30 μM (%) 2 103 3 74.8 6 88.7 7 94 879.6 10 72.7 14 94.3 15 79.9 16 88.3 17 95.2 19 79.4 23 83.5 24 76.9 2591 26 74.9 28 79.3 33 79.4 35 79.8 36 100.7 37 74.9 38 99.3 39 85.9 4283.6 43 84.1 44 73.8 45 82.6 46 77.3 48 88.1 49 71.6 55 75.1 57 78.7 6177.1 62 76.9 65 74.6 67 73.5 68 88.4 69 79.9 70 71.4 71 72.3 72 76.4 7387.9 74 88.2 75 99.1 76 93.3 78 94.2 79 79.6 80 90.6 81 95.1 82 81.4 83102.6 84 101.6 85 108.8 86 102.7 87 100.8 88 90.3 89 82.8 90 89.3 9180.9 92 78.9 93 88.2 94 94.4 95 83.2 96 97.2 99 76.9 100 89.2 102 73.8103 88.6 106 85.9 107 86 110 86.8 111 91 113 78.7 114 77.2 115 87.9 11884 119 71 120 71.5 121 84.4 122 71.4 123 83.2 124 86.3 125 86.7 127 74.7128 70.9 129 80.4 130 96 131 110.1 132 106

As shown in Table 2, the compound of the present invention inducedcellular calcium influx in an AMPA receptor-expressing cells. That is tosay the compound of the present invention has an AMPA receptorpotentiator effect.

Experimental Example 2 Novel Object recognition test (1) animals

Male Long Evans rats were supplied by Japan SLC, and used at 7-week-oldin the experiments. After arrival to the vivarium, animals were alloweda minimum of 1 week for acclimation. They were housed under a 12:12-hlight/dark cycle in a temperature- and humidity-controlled laboratoryand allowed food and water ad libitum.

(2) Drug Administration

A test compound was suspended in 0.5% methylcellulose in distilled waterand orally administered (p.o.). All test 15 compounds were dosed in avolume of 2 mL/kg body weight for rats.

(3) Novel Object Recognition Test

Novel object recognition test is a test system utilizing the novelobject preference characteristics of rodents. This novel objectrecognition test consists of two trials, “acquisition trial” and“retention trial”, and, when an interval between these two trials isshort, rodents spend a longer period for novel object explorationbehaviors, and the preference dissipates as the interval gets longer.From this, the behavioral change in the novel object recognition test isconsidered to reflect the rodents' memory of the object during theacquisition trial. In this experimental example, the retention trial wascarried out 48 hr after the acquisition trial. On the day before thetest, for acclimation, Long-Evans ats were allowed to freely move aboutthe test box (40×40×50 cm) for 10 minutes. On the test day, the ratswere acclimated to the test room for about 1 hr prior to the test. Thetest compound (Compound A (Example 14), Compound B (Example 48), 1mg/kg) were orally administered to the rats twice 1 hr before theacquisition trial and 1 hr before the retention trial. For theacquisition trial, two identical objects (A1, A2) were placed in thetest box. The rats were put in the test box for 3 min, and the durationcontacting each object was measured. The retention trial was carried out48 hr after the acquisition trial. For the retention trial, the familiarobject (A3) used for the acquisition trial and the novel object (B)different shape from A3 were placed in the test box. The rats were putin the test box for 3 min. The duration contacting each object in theacquisition trial and the retention trial, and the novel objectinteraction (%) was calculated. The novel object interaction (%) wasexpressed as (the duration contacting the novel object)/[(the durationcontacting the novel object)+(the duration contacting the familiarobject)]×100 (%) at mean ±standard error. The results are shown in Table3.

TABLE 3 Novel Object Interaction Dose (%) 0 mg/kg 1 mg/kg Compound A(Example 14) 51.42 ± 2.05 61.94 ± 2.33 Compound B (Example 48) 52.39 ±1.07 61.42 ± 2.61

As shown in Table 3, Compounds A and B increased the novel objectinteraction. That is to say, the compound of the present invention has acognition function-improving action.

Preparation Example 1. Capsule

(1) compound obtained in Example 1 40 mg (2) lactose 70 mg (3)microcrystalline cellulose 9 mg (4) magnesium stearate 1 mg 1 capsule120 mg

(1), (2), (3) and 1/2 of (4) are blended and granulated. Thereto isadded the remaining (4) and the whole is sealed in a gelatin capsule.

2. Tablet

(1) compound obtained in Example 1 40 mg (2) lactose 58 mg (3)cornstarch 18 mg (4) microcrystalline cellulose 3.5 mg (5) magnesiumstearate 0.5 mg 1 tablet 120 mg

(1), (2), (3), 2/3 of (4) and 1/2 of (5) are blended and granulated.Thereto is added the remaining (4) and (5) and the mixture iscompression formed into a tablet.

INDUSTRIAL APPLICAILITY

The compound of the present invention has an AMPA receptor potentiatoreffect, and is expected to be useful as an agent for the prophylaxis ortreatment of depression, Alzheimer's disease, schizophrenia, attentiondeficit hyperactivity disorder (ADHD) and the like.

This application is based on patent application No. 2017-195904 filed onOct. 6, 2017 in Japan, the contents of which are encompassed in fullherein.

[Sequence Listing Free Text]

SEQ ID NO: 1 is a forward primer for GluR¹ flip cDNA. SEQ ID NO: 2 is areverse primer for GluR¹ flip cDNA. SEQ ID NO: 3 is a forward primer forstargazin cDNA. SEQ ID NO: 4 is a reverse primer for stargazin cDNA.

1. A compound represented by the formula (I):

wherein R¹ and R² are each independently a hydrogen atom or asubstituent, or R¹ and R² are bonded to each other to form, togetherwith the adjacent nitrogen atom, an optionally further substitutednon-aromatic nitrogen-containing heterocycle, X is CR⁴ or N, R³, R⁴, R⁵and R⁶ are each independently a hydrogen atom, a halogen atom, anoptionally substituted C₁₋₆ alkyl group or an optionally substitutedC₁₋₆ alkoxy group, and Ring A is a 6-membered aromatic ring optionallyfurther substituted by 1 to 4 substituents selected from (i) a halogenatom, (ii) a C₁₋₆ alkyl group and (iii) a C₁₋₆ alkoxy group, or a saltthereof.
 2. The compound or salt according to claim 1, wherein R¹ and R²are each independently (1) a hydrogen atom, (2) a C₁₋₆ alkyl groupoptionally substituted by 1 to 3 substituents selected from (a) ahalogen atom, (b) a cyano group, (c) a hydroxy group, (d) a C₁₋₆ alkoxygroup, (e) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to 3cyano groups, and (f) a 3-to 14-membered non-aromatic heterocyclicgroup, (3) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to 3C₁₋₆ alkyl groups optionally substituted by 1 to 3 halogen atoms, or (4)a 3-to 14-membered non-aromatic heterocyclic group, or R¹ and R² arebonded to each other to form, together with the adjacent nitrogen atom,a 3-to 14-membered non-aromatic nitrogen-containing heterocycleoptionally further substituted by 1 to 3 substituents selected from (a)a halogen atom, (b) a cyano group, (c) a hydroxy group, (d) a C₁₋₆ alkylgroup optionally substituted by 1 to 3 substituents selected from (i) ahalogen atom, and (ii) a hydroxy group, (e) a C₁₋₆ alkoxy groupoptionally substituted by 1 to 3 halogen atoms, and (f) a C₃₋₁₀cycloalkyl group; R³ is (1) a hydrogen atom, (2) a halogen atom, or (3)a C₁₋₆ alkyl group; X is CH or N; R⁵ is a hydrogen atom; R⁶ is ahydrogen atom; and Ring A is a benzene ring optionally furthersubstituted by 1 or 2 halogen atoms.
 3. The compound or salt accordingto claim 1, wherein R¹ and R² are each independently (1) a hydrogenatom, (2) a C₁₋₆ alkyl group optionally substituted by 1 to 3substituents selected from (a) a halogen atom, (b) a cyano group, (c) ahydroxy group, (d) a C₁₋₆ alkoxy group, (e) a C₃₋₆ cycloalkyl groupoptionally substituted by 1 to 3 cyano groups, and (f) an oxetanylgroup, (3) a C₃₋₆ cycloalkyl group optionally substituted by 1 to C₁₋₆alkyl groups optionally substituted by 1 to 3 halogen atoms, (4) atetrahydrofuryl group, or (5) a tetrahydropyranyl group, or R¹ and R²are bonded to each other to form, together with the adjacent nitrogenatom, (1) a morpholine ring optionally further substituted by 1 to 3substituents selected from (a) a halogen atom, (b) a cyano group, and(c) a C₁₋₆ alkyl group optionally substituted by 1 to 3 halogen atoms,(2) a pyrrolidine ring optionally further substituted by 1 to 3substituents selected from (a) a halogen atom, (b) a cyano group, (c) ahydroxy group, (d) a C₁₋₆ alkyl group optionally substituted by 1 to 3substituents selected from (i) a halogen atom, and (ii) a hydroxy group,and (e) a C₁₋₆ alkoxy group optionally substituted by 1 to 3 halogenatoms, (3) a piperidine ring optionally further substituted by 1 to 3substituents selected from (a) a halogen atom, (b) a cyano group, (c) ahydroxy group, (d) a C₁₋₆ alkyl group optionally substituted by 1 to 3halogen atoms, and (e) a C₁₋₆ alkoxy group, (4) an azetidine ringoptionally further substituted by 1 to 3 substituents selected from (a)a halogen atom, (b) a hydroxy group, (c) a C₁₋₆ alkyl group, (d) a C₁₋₆alkoxy group, and (e) a C₃₋₆ cycloalkyl group, (5) an oxazepane ringoptionally further substituted by 1 to 3 halogen atoms, (6) a2,3-dihydro-1H-pyrrolo[2,3-b]pyridine ring, (7) a1-oxa-7-azaspiro[3.5]nonane ring, or (8) a2-oxa-5-azabicyclo[4.1.0]heptane ring; R³ is (1) a hydrogen atom, (2) ahalogen atom, or (3) a C₁₋₆ alkyl group; X is CH or N; R⁵ is a hydrogenatom; R⁶ is a hydrogen atom; and Ring A is a benzene ring optionallyfurther substituted by 1 or 2 halogen atoms.
 4. The compound or saltaccording to claim 1, wherein R¹ is a hydrogen atom, and R² is atetrahydropyranyl group, or R¹ and R² are bonded to each other to form,together with the adjacent nitrogen atom, (1) a morpholine ringoptionally further substituted by 1 to 3 C₁₋₆ alkyl groups, or (2) apyrrolidine ring optionally further substituted by 1 to 3 cyano groups;R³ is (1) a hydrogen atom, (2) a halogen atom, or (3) a C₁₋₃ alkylgroup; X is CH; R⁵ is a hydrogen atom; 5 R⁶ is a hydrogen atom; and RingA is a benzene ring.
 5. The compound or salt according to claim 1,wherein R¹ is a hydrogen atom, and R² is a tetrahydropyranyl group, orR¹ and R² are bonded to each other to form, together with the adjacentnitrogen atom, a morpholine ring optionally further substituted by oneC₁₋₆ alkyl group; R³ is (1) a halogen atom, or (2) a C₁₋₃ alkyl group; Xis CH; R⁵ is a hydrogen atom; R⁶ is a hydrogen atom; and Ring A is abenzene ring. 6.3-Bromo-9-(4-(morpholin-4-ylcarbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one,or a salt thereof. 7.3-Bromo-9-(4-(((2S)-2-methylmorpholin-4-yl)carbonyl)phenyl)-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-4-one,or a salt thereof. 8.4-(3-Methyl-4-oxo-2-(trifluoromethyl)-4H-pyrido[1,2-a]pyrimidin-9-yl)-N-((3S)-tetrahydro-2H-pyran-3-yl)benzamide,or a salt thereof.
 9. A medicament comprising the compound or saltaccording to claim
 1. 10. The medicament according to claim 9, which isan AMPA receptor potentiator.
 11. The medicament according to claim 9,which is an agent for the prophylaxis or treatment of depression,Alzheimer's disease, schizophrenia or attention deficit hyperactivitydisorder.
 12. The compound or salt according to claim 1 for use in theprophylaxis or treatment of depression, Alzheimer's disease,schizophrenia or attention deficit hyperactivity disorder.
 13. A methodof enhancing AMPA receptor function in a mammal, which comprisesadministering an effective amount of the compound or salt according toclaim 1 to the mammal.
 14. A method for the prophylaxis or treatment ofdepression, schizophrenia, Alzheimer's disease or attention deficithyperactivity disorder in a mammal, which comprises administering aneffective amount of the compound or salt according to claim 1 to themammal.
 15. Use of the compound or salt according to claim 1 for themanufacture of an agent for the prophylaxis or treatment of depression,Alzheimer's disease, schizophrenia or attention deficit hyperactivitydisorder.